Anderton, B. H. (2002). "Ageing of the brain." Mech Ageing Dev 123(7): 811-7.
The brains of individuals who are cognitively normal show age-related changes that include an overall reduction in the brain volume and weight and enlargement of the brain ventricles. These changes are partly the result of nerve cell loss but accurate estimates of neuronal loss are notoriously difficult to make. There is loss of synapses and dendritic pruning in the aged brain but in selected areas rather than globally. Neurofibrillary tangles and senile plaques are the neuropathological hallmark of Alzheimer's disease in which they are more abundant and widespread than in the brains of intellectually intact elderly people. Alzheimer's disease has, therefore, been regarded as accelerated brain ageing, however, since there is a strong genetic contribution to developing the disease it implies that it may not be the inevitable, even if frequent, consequence of old age. The interplay between genetic and environmental factors probably determines the degree of pathological brain ageing and whether or not individuals develop dementia.

Apaydin, H., J. E. Ahlskog, et al. (2002). "Parkinson disease neuropathology: later-developing dementia and loss of the levodopa response." Arch Neurol 59(1): 102-12.
OBJECTIVE: To investigate the neuropathologic substrate for dementia occurring late in Parkinson disease (PD). DESIGN: We identified 13 patients with a clinical diagnosis of PD who experienced dementia at least 4 years after parkinsonism onset (mean, 10.5 years) and subsequently underwent postmortem examination. Despite levodopa therapy, 9 patients later became severely impaired and nonambulatory, requiring total or near-total care; this included 4 patients treated with 1200 mg/d or more of levodopa (with carbidopa), which was consistent with loss of the levodopa response. These 13 patients were compared with 9 patients clinically diagnosed as having PD, but without dementia, who had undergone autopsies. RESULTS: Twelve of 13 PD patients with dementia had findings of diffuse or transitional Lewy body disease as the primary pathologic substrate for dementia; 1 had progressive supranuclear palsy. This pathology also apparently accounted for the levodopa refractory state. Among the 12 PD patients with dementia, mean and median Lewy body counts were increased nearly 10-fold in neocortex and limbic areas compared with PD patients without dementia (P< or =.002). Alzheimer pathology was modest. Only one patient met the criteria defined by the National Institute on Aging and the Reagan Institute Working Group on the Diagnostic Criteria for the Neuropathologic Assessment of Alzheimer's Disease for "intermediate probability of Alzheimer's disease." There were, however, significant correlations between neocortical Lewy body counts and senile plaques as well as neurofibrillary tangles. Senile plaque counts did not significantly correlate with tangle counts in any of the analyzed nuclei. Arteriolar disease may have contributed to the clinical picture in 2 patients. CONCLUSIONS: Diffuse or transitional Lewy body disease is the primary pathologic substrate for dementia developing later in PD. This same pathologic substrate seemed to account for end-stage, levodopa refractory parkinsonism. The occurrence of Alzheimer pathology was modest, but was highly correlated with Lewy body pathology, suggesting common origins or one triggering the other.

Augustinack, J. C., J. L. Sanders, et al. (2002). "Colocalization and fluorescence resonance energy transfer between cdk5 and AT8 suggests a close association in pre-neurofibrillary tangles and neurofibrillary tangles." J Neuropathol Exp Neurol 61(6): 557-64.
Cyclin-dependent kinase 5 (cdk5) is a serine/threonine kinase that, when activated, induces neurite outgrowth. Recent in vitro studies have shown that cdk5 phosphorylates tau at serine 199, serine 202, and threonine 205 and that p25, an activator of cdk5, is increased in Alzheimer disease (AD). Since tau is hyperphosphorylated at these sites in neurofibrillary tangles, we examined brain tissue from patients with AD and normal elderly control cases to determine whether cdk5 and these phosphoepitopes colocalize in neurofibrillary tangles. Adjacent temporal lobe sections were double immunostained with a polyclonal anti-cdk5 and monoclonal AT8 (which recognizes phosphorylated serine 199, serine 202, and threonine 205 in tau) antibodies. A subset of AT8 phosphotau-positive neurons was immunoreactive for cdk5 in entorhinal (area 28) and perirhinal (area 35) cortices and CA1 of the hippocampus. We assessed the ratio of cdk5-positive cells to AT8-positive cells and found that there is a higher degree of colocalization in pre-neurofibrillary tangles as opposed to intraneuronal and extraneuronal neurofibrillary tangles. We further examined colocalization using fluorescence resonance energy transfer. This suggests a close, stable intermolecular association between cdk5 and phosphorylated tau, consistent with phosphorylation of tau by cdk5 in AD brain.

Augustinack, J. C., A. Schneider, et al. (2002). "Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease." Acta Neuropathol (Berl) 103(1): 26-35.
Microtubule associated protein tau is abnormally phosphorylated in Alzheimer's disease (AD) and aggregates as paired helical filaments (PHFs) in neurofibrillary tangles (NFTs). We show here that the pattern of tau phosphorylation correlates with the loss of neuronal integrity. Studies using 11 phosphorylation dependent tau antibodies and a panel of AD cases of varying severity were evaluated in terms of three stages of neurofibrillary tangle development: (1) pre-neurofibrillary tangle, (2) intra-, and (3) extra-neuronal neurofibrillary tangles. The pretangle state, in which neurons display nonfibrillar, punctate regions in the cytoplasm, sound dendrites, somas, and nuclei, was observed especially with phospho-tau antibodies TG3 (pT231), pS262, and pT153. Intraneuronal neurofibrillary tangles are homogenously stained with fibrillar tau structures, which were most prominently stained with pT175/181, 12E8 (pS262/pS356), pS422, pS46, pS214 antibodies. Extracellular NFTs, which contain substantial filamentous tau, are most prominently stained with AT8 (pS199/pS202/pT205), AT100 (pT212/pS214), and PHF-1 (pS396/pS404) antibodies, which also stain intracellular NFT. The sequence of early tau phosphorylation suggests that there are events prior to filament formation that are specific to particular phosphorylated tau epitopes, leading to conformational changes and cytopathological alterations.

Avila, J., F. Lim, et al. (2002). "Tau function and dysfunction in neurons: its role in neurodegenerative disorders." Mol Neurobiol 25(3): 213-31.
Alzheimer's disease (AD) is the most usual neurodegenerative disorder leading to dementia in the aged human population. It is characterized by the presence of two main brain pathological hallmarks: senile plaques and neurofibrillary tangles (NFTs). NFTs are composed of fibrillar polymers of the abnormally phosphorylated cytoskeletal protein tau.

Bacskai, B. J., W. E. Klunk, et al. (2002). "Imaging Amyloid-beta Deposits In Vivo." J Cereb Blood Flow Metab 22(9): 1035-41.
Alzheimer disease (AD) is an illness that can only be diagnosed with certainty with postmortem examination of brain tissue. Tissue samples from afflicted patients show neuronal loss, neurofibrillary tangles (NFTs), and amyloid-beta plaques. An imaging technique that permitted detection of NFTs or amyloid-beta plaques would be extremely valuable. For example, chronic imaging of senile plaques would provide a readout of the efficacy of experimental therapeutics aimed at removing these neuropathologic lesions. This review discusses the available techniques for imaging amyloid-beta deposits in the intact brain, including magnetic resonance imaging, positron emission tomography, single photon emission computed tomography, and multiphoton microscopy. A variety of agents that target amyloid-beta deposits specifically have been developed using one or several of these imaging modalities. The difficulty in developing these tools lies in the need for the agents to cross the blood-brain barrier while recognizing amyloid-beta with high sensitivity and specificity. This review describes the progress in developing reagents suitable for imaging of senile plaques.

Beeber, C. and F. J. Kieras (2002). "Characterization of the chondroitin sulfates in wild type Caenorhabditis elegans." Biochem Biophys Res Commun 293(5): 1374-6.
The purpose of this study was to isolate and characterize the GAGs from the wild type nematode Caenorhabditis elegans in preparation for the characterization of the transgenic form constructed by Link [Proc. Natl. Acad. Sci. USA 92 (1995) 9368] which expresses various forms of beta-peptide (or A4 peptide). This peptide forms deposits very similar to the ones found in the neuritic plaques and neurofibrillary tangles in Alzheimer disease (AD). Characterization has been accomplished by degradation with specific enzymes and analysis of the products by TLC and HPLC. The results were compared with earlier works and shown to differ in disaccharide content.

Bhagat, Y. A., A. Obenaus, et al. (2002). "Evolution of beta-amyloid induced neuropathology: magnetic resonance imaging and anatomical comparisons in the rodent hippocampus." Magma 14(3): 223-32.
Alzheimer's disease (AD) is characterized by the anatomical appearance of beta-amyloid (betaA) plaques and neurofibrillary tangles. These changes are also associated with cyclical inflammation, oxidative damage and, as inferred from the autopsied brains of patients, progressive injury to neurons. Here, we report the short-term effects of an intrahippocampal injection of the toxic betaA peptide fragment 25-35 in rats using quantitative magnetic resonance imaging (MRI) methods. Physiological changes within the cornu ammonis 1 (CA1) region of the hippocampus were monitored using a 1.5 T scanner at time points of 0.25, 1 and 24 h, and 7 and 14 days post injection. Spin echo T2-weighted (T2W) and diffusion weighted (DW) images were sequentially acquired. Apparent diffusion coefficients (ADC) were calculated and compared with histological alterations. A significant elevation in mean ADC values (17%) was observed in the ipsilateral CA1 at 14 days. The ADC changes were associated with disrupted pyramidal cells and nuclear lysis observed in histological sections. The contralateral CA1 exhibited a significant decrease in mean ADC of 15% at 14 days post treatment. Histological changes in the contralateral hippocampus suggested decreased neuronal density. T2W maps revealed no significant differences between the active betaA 25-35 fragment and its non-active analog, betaA 35-25. In conclusion, these results, based on changes in hippocampal ADC, demonstrate that the betaA 25-35 treatment induced pathology consistent with edema and cellular necrosis. This is the first report describing the evolution of AD-like pathology in an animal model using DW imaging.

Bian, F., R. Nath, et al. (2002). "Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25-transgenic mice." J Comp Neurol 446(3): 257-66.
Neurofibrillary tangles, one of the pathologic hallmarks of Alzheimer's disease (AD), are composed of abnormally polymerized tau protein. The hyperphosphorylation of tau alters its normal cellular function and is thought to promote the formation of neurofibrillary tangles. Growing evidence suggests that cyclin-dependent kinase 5 (cdk5) plays a role in tau phosphorylation, but the function of the enzyme in tangle formation remains uncertain. In AD, cdk5 is constitutively activated by p25, a highly stable, 25kD protein thought to be increased in the AD brain. To test the hypothesis that p25/cdk5 interactions promote neurofibrillary pathology, we created transgenic mouse lines that overexpress the human p25 protein specifically in neurons. Mice with high transgenic p25 expression have augmented cdk5 activity and develop severe hindlimb semiparalysis and mild forelimb dyskinesia beginning at approximately 3 months of age. Immunohistochemical and ultrastructural analyses showed widespread axonal degeneration with focal accumulation of tau in various regions of the brain and, to a lesser extent, the spinal cord. However, there was no evidence of neurofibrillary tangles in neuronal somata or axons, nor were paired helical filaments evident ultrastructurally. These studies confirm that p25 overexpression can lead to tau abnormalities and axonal degeneration in vivo but do not support the hypothesis that p25-related induction of cdk5 is a primary event in the genesis of neurofibrillary tangles.

Bigio, E. H., L. S. Hynan, et al. (2002). "Synapse loss is greater in presenile than senile onset Alzheimer disease: implications for the cognitive reserve hypothesis." Neuropathol Appl Neurobiol 28(3): 218-27.
In the past, 'Alzheimer disease' (AD) referred to pathologic AD with clinical onset of dementia in the presenium, while 'senile dementia of the Alzheimer type' (SDAT) referred to senile onset AD. Because AD appears clinically homogeneous regardless of age of onset, the two subtypes in more recent years have not been distinguished. Pathologic differences have been noted, but synapse loss has not previously been compared between the two groups. Hypothesizing that synapse loss would be greater in presenile onset than senile onset AD, we compared synapse loss, as well as Alzheimer pathology in presenile and senile onset AD, using an ELISA method to quantify synaptophysin. Synaptophysin was significantly lower in presenile than senile AD in right frontal and bilateral parietal lobes. Neuritic plaque counts were significantly higher in presenile than senile AD in bilateral frontal and parietal lobes. Semi-quantitative evaluation of neurofibrillary tangles revealed significantly more tangles in bilateral frontal and parietal lobes in presenile than senile AD. Brain weight was significantly lower in presenile than senile AD. The differences in synapse loss and Alzheimer-type pathology in presenile and senile onset AD support the hypothesis that 'cognitive reserve' protects the human brain from neurodegenerative disease.

Bogdanovic, N., E. Corder, et al. (2002). "APOE polymorphism and clinical duration determine regional neuropathology in Swedish APP(670, 671) mutation carriers: implications for late-onset Alzheimer's disease." J Cell Mol Med 6(2): 199-214.
Neurofibrillary changes throughout the brain were investigated for three relatives who carried the Swedish APP(670, 671) mutation which causes overproduction of Abeta40 and Abeta42. They differed in terms of APOE genotype, age at the onset of dementia, and disease duration (P1: epsilon2/3, age 57, 11 years; P2: epsilon2/3, age 61, 5 years; P3: epsilon4/4, age 44, 12 years). For each subject, paraffin-embedded sections from diverse anatomically and cytoarchitectonically well-preserved regions were stained using the modified Bielschowsky method. Neurofibrillary tangles (NFT) and neuritic plaques (NP) were counted, and the area occupied by plaque estimated (%NP). In addition, sections from the medial frontal gyrus were stained with monoclonal antibodies to APOE. The regional patterns of neurofibrillary changes were consistent with those for late-onset AD. Longer disease duration was associated with further accumulations in earlier-affected areas, with superficial cortical layers consistently containing higher %NP than deep layers. APOE epsilon4/4 was associated with deeper limbic and frontal NFT, with an excess of NP (especially in the outer parietal cortex) which stained heavily for APOE - as well as with very early onset. APP(670, 671) mutation carriers demonstrate regional brain neurofibrillary changes characteristic of late-onset Alzheimer's disease with evidence for more Abeta deposition for epsilon4/4 than epsilon2/3. This raises the possibility that early Braak Stage I-II lesions might also follow this pattern of promotion.

Borghi, R., L. Giliberto, et al. (2002). "Increase of cdk5 is related to neurofibrillary pathology in progressive supranuclear palsy." Neurology 58(4): 589-92.
BACKGROUND: Progressive supranuclear palsy (PSP) is characterized by a pure neurofibrillary tau pathology involving mainly basal ganglia and brainstem nuclei. In addition to a haplotype of the tau gene potentially favoring tau aggregation, lipoperoxidation has been shown to be associated with PSP tau pathology. OBJECTIVE: To analyze cdk5/p35 complex, a kinase that regulates neurite outgrowth, as a potential cellular mechanism underlying tau phosphorylation in brain tissues from PSP and control cases and comparatively in cerebral cortex from subjects with AD. METHODS: Cdk5/p35 protein levels and distribution were evaluated by immunoblotting and immunocytochemistry in brain regions from seven PSP, six AD, and seven control cases, with similar postmortem intervals. RESULTS: Total cdk5 protein levels were significantly increased by more than threefold in PSP tissue and were augmented in PSP neurons, codistributed with tau immunoreactivity. P35, the regulatory subunit of cdk5, was degraded by postmortem proteolysis to the same extent in PSP, AD, and control tissues. CONCLUSIONS: The proteolysis in vivo of p35, the regulatory subunit of the kinase, is not ascertainable because it is masked by its postmortem degradation. The study, however, indicates that in PSP, the alteration of cdk5 is different from that described in AD and suggests that the absence of amyloid beta protein deposition may account for the different pathways responsible for the same kinase activation.

Boutajangout, A., K. Leroy, et al. (2002). "Increased tau phosphorylation but absence of formation of neurofibrillary tangles in mice double transgenic for human tau and Alzheimer mutant (M146L) presenilin-1." Neurosci Lett 318(1): 29-33.
Neurofibrillary tangles, composed of tau proteins, are a key lesion observed in sporadic forms of Alzheimer's disease and in familial forms associated with mutations of presenilin-1 (PS1). We have generated a double transgenic mouse line expressing a human tau isoform and a mutated form of PS1 (M146L) in neurons. Increased expression of the PS1 holoprotein was observed in the tau/PS1 transgenic mice and the proteolytic fragments of PS1 did not appear to be modified. A somatodendritic accumulation of the transgenic tau and an increase in tau phosphorylation were observed in both tau- and tau/PS1 transgenic mice. Neurofibrillary tangles were not observed in animals analyzed up to 17 months. Immunoprecipitation of tau from brain homogenates demonstrated its binding with active glycogen synthase kinase-3beta in control, tau- and tau/PS1 transgenic lines. These results suggest that overexpression of this Alzheimer mutant PS1 in vivo is not by itself sufficient to induce the formation of neurofibrillary tangles, even in neurons co-expressing and accumulating a human tau isoform.

Bozikas, V. P., E. Kovari, et al. (2002). "Neurofibrillary tangles in elderly patients with late onset schizophrenia." Neurosci Lett 324(2): 109-12.
The objective of the present study was to examine whether neurofibrillary tangles densities are increased in elderly patients with late-onset schizophrenia (LOS). A neuropathological examination was performed in 32 consecutive autopsy brain specimens of ten patients with early-onset schizophrenia (EOS; onset of symptoms before the age of 40 years), eight patients with LOS (onset of symptoms after the age of 40 years) and 14 age-matched controls with no known neuropsychiatric disorder. Neurofibrillary tangle densities observed in the CA1 field of the hippocampus, the enthorhinal cortex, and the inferior temporal cortex in patients with LOS, EOS, and controls were not significantly different. All patients with EOS or LOS had Braak stages of III or less, which may correspond to normal aging. Thus, patients with schizophrenia, regardless of the age of onset of their symptoms, are no more prone to the development of Alzheimer's disease than the general population.

Briani, C., S. Ruggero, et al. (2002). "Combined analysis of CSF betaA42 peptide and tau protein and serum antibodies to glycosaminoglycans in Alzheimer's disease: preliminary data." J Neural Transm 109(3): 393-8.
Neuropathological hallmarks of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles, containing betaA(42) peptide and tau protein, respectively. Amyloid plaques contain also glycosaminoglycans (GAGs). Whereas cerebrospinal fluid (CSF) levels of betaA(42) peptide and tau protein have been demonstrated as potential markers of Alzheimer's disease (AD), no data are available for GAGs. We determined (Elisa) tau and betaA(42) CSF levels, as well as serum antibodies to GAGs in 9 AD patients, and the values were analyzed in relation to age and severity of the disease. Beta-A42 and tau CSF levels were significantly reduced and increased, respectively, in AD patients when compared to controls, but they did not correlate with the severity of the disease. Despite their role in amyloidogenesis, we did not find evidence for the use of GAGs as diagnostic marker of AD.

Buee, L., M. Hamdane, et al. (2002). "[Tau story: from frontotemporal dementia to other tauopathies]." J Soc Biol 196(1): 103-8.
Tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they play an important role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network. Tau proteins are translated from a single gene located on chromosome 17. Their expression is developmentally regulated by an alternative splicing mechanism and six different isoforms exist in the human adult brain. Tau proteins are the major constituents of fibrillar lesions described in Alzheimer's disease and numerous neurodegenerative disorders referred to as 'tauopathies'. Molecular analysis has revealed that an abnormal phosphorylation might be one of the important events in the process leading to their aggregation. Moreover, a specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution could characterize each of these disorders. Finally, the recent discovery of tau gene mutations in fronto-temporal dementia with parkinsonism linked to chromosome 17 has reinforced the direct role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies. Conversely, recent data in myotonic dystrophy has demonstrated that indirect effect (CTG repeat expansion) leading to variations in tau alternative splicing also produce neurofibrillary degeneration.

Callahan, L. M., W. A. Vaules, et al. (2002). "Progressive reduction of synaptophysin message in single neurons in Alzheimer disease." J Neuropathol Exp Neurol 61(5): 384-95.
The data presented here examine 2 hypotheses: 1) that viable but vulnerable single neurons remaining in the Alzheimer brain lose synaptic markers, and 2) that the extent of this loss is related to the disease state of these single neurons when disease state is defined by immunoreactivity. We used double immunohistochemistry (IHC) to define neurofibrillary tangle (NFT) and phosphorylation status of tau at selected defined epitopes. This double IHC was combined with quantitative in situ hybridization for message for the synaptic marker, synaptophysin, in 1,127 single hippocampal CA1 pyramidal neurons from 15 Alzheimer disease (AD) and 4 control cases. We found that there is a graded, progressive, decrease of synaptophysin message expressed by single neurons related to immunohistochemical markers of tau status, and that neurons in similar immunohistochemically defined classes show similar losses of synaptophysin message regardless of whether they were sampled from clinical control brains or advanced AD. The resulting conclusions are consistent with a suggestion that differences among clinically defined AD and control status are defined by the numbers of neurons in various disease states.

Casanova, M. F., J. R. Stevens, et al. (2002). "Disentangling the pathology of schizophrenia and paraphrenia." Acta Neuropathol (Berl) 103(4): 313-20.
With increasing longevity, the number of older schizophrenic patients is growing. Previous criteria used the age of symptom onset to differentiate between the late manifestations of early-onset schizophrenia and late-onset schizophreniform disorders. Current DSM-IV or ICD 10 nomenclatures do not differentiate between early- and late-onset schizophrenia. Many decades of repeated failures to provide for distinguishing neuropathological findings have prompted narrower definition criteria. Since psychotic or schizophreniform symptoms in old age may be a manifestation of Alzheimer's disease, we attempted to base a distinction between both early- and late-onset schizophrenia on the presence of degenerative changes. This study examined the brains of 64 schizophrenic patients and 18 controls immunocytochemically for tau and amyloid staining. We divided patients according to their ages at the onset of symptoms: <40, >40. Using Braak's classification, we assessed the presence of neurofibrillary pathology. Stages III and IV were observed in 11.1% (2/18) of controls, 36.7% (11/30) of early-onset schizophrenics (<40) and 58.8% (20/34) of late-onset (>40) schizophrenics (chi2=11.39, P =0.003). Stages V and VI (definite Alzheimer's disease) did not significantly differ among groups (chi2=3.6, P =0.165). Astrocytes, subependymal and fibroblastic, also exhibited tau-positive tangles. Chi-square analysis of the data revealed a significant association between tau-positive glial tangles and Braak staging ( P =0.002). Amyloid deposits were sparse in comparison to tau-related changes. The restricted limbic tauopathy not only affected a majority of patients with late-onset schizophrenia (19 female: 1 male among positive cases) ( P =0.048) but also appeared in one-third of those elderly schizophrenic patients whose symptom onset occurred before 40 years of age (8 female: 3 male among positive cases) ( P =0.048). The resultant changes define a type of neuronal cytoskeletal disruption that alters the flow of information through the hippocampus and provides a useful clinico-pathological correlate to a group of patients until recently diagnosed as schizophrenic.

Colton, C. A., C. M. Brown, et al. (2002). "Apolipoprotein-E allele-specific regulation of nitric oxide production." Ann N Y Acad Sci 962: 212-25.
Cognitive decline and dementia are key features of Alzheimer's disease (AD) that result from failure of neuronal function. Affected neurons demonstrate indices of nitrosative stress resulting from changes in nitric oxide (NO) mediated redox balance. Neurofibrillary tangles, a characteristic neuropathologic feature of AD, and dysfunctional neurons frequently display 3-nitrotyrosine or other markers of nitrosative stress and immunoreactive nitric oxide synthase (NOS), suggesting that NOS-containing neurons are affected in AD. Our previous studies showed that apolipoprotein E treatment of macrophages increased NO production. Using transgenic mouse models expressing human apoE2, apoE3, or apoE4 protein isoforms and no mouse apoE, we now report an isoform specific difference in microglial NO production. Mice expressing the apoE4 protein isoform have a greater NO production than mice expressing the apoE3 protein isoform. The supply of arginine, the sole substrate for NOS, is dependent on cationic amino acid transporters (CATs) that also demonstrate a similar pattern of apoE isoform dependency. Although arginine transport is greater in APOE4 microglia, this effect is not limited to tissue macrophages. Cortical neurons in primary culture from APOE4 transgenic mice exhibit a similar increase in arginine uptake over neurons cultured from APOE3 mice. The inappropriate levels of arginine transport and of NO in the presence of the APOE4 compared to the APOE3 gene and its products are likely to have significant impact in the CNS.

Cummings, B. J., A. J. Mason, et al. (2002). "Optimization of techniques for the maximal detection and quantification of Alzheimer's-related neuropathology with digital imaging." Neurobiol Aging 23(2): 161-70.
Prior to undertaking quantitative neuropathological studies of Alzheimer's disease, methods for detecting plaques and tangles must be optimized. While suitable antibodies have been developed with great sensitivity, specificity, and reliability, there is no standard pre-treatment protocol for key AD-related pathology. It is well known that formic acid treatment enhances the detection of beta-amyloid. But what concentration of formic acid is best; can similar methods enhance the detection of tau-related pathology? This study compared multiple antigen retrieval techniques (e.g. boiling in citrate or glycine buffer, microwaves, formic acid concentrations), to develop an optimal, standardized protocol for quantitative digital microscopy. Free-floating (40 microm) and paraffin-embedded (12 microm) sections of formalin fixed frontal cortex from mild, moderate, and severe AD cases (n = 18) were pretreated with fifteen different protocols and stained with each of the following antibodies: beta42, PHF-1, MC-1 and AT8. Random fields were digitally captured and images were thresholded to select for positively stained areas versus background (e.g. "load"). As previously reported, high concentrations of formic acid were extremely effective in enhancing the detection of beta-amyloid; as much as a 2-fold enhancement in Abeta "load" values were observed. Surprisingly, tau-related pathology detection also increased significantly following pretreatment. Depending on the antibody, between a 3-fold and 6-fold enhancement was possible relative to no pretreatment. Comparable results were found in paraffin-embedded sections. Similar enhancements in the detection of pathology were obtained following 99% formic acid exposure, microwaving in citrate buffer (pH 9.0) or exposure to 99% formic acid then boiling in citrate buffer (pH 6.0). Because the latter treatments were often harsh on the tissue and more difficult to control, we recommend a standard tissue pretreatment of 99% formic acid for seven minutes for both beta-amyloid and tau-related pathology.

Damadzic, R., S. Shuangshoti, et al. (2002). "Neuritic pathology is lacking in the entorhinal cortex, subiculum and hippocampus in middle-aged adults with schizophrenia, bipolar disorder or unipolar depression." Acta Neuropathol (Berl) 103(5): 488-94.
Earlier reports have provided conflicting results regarding the association between Alzheimer's disease (AD) and mental disorders. Using a well-characterized postmortem series of 40 middle-aged human brains, we have performed quantitative analysis of neurofibrillary tangles and senile plaques in the entorhinal cortex, subiculum and rostral hippocampus in 9 subjects with schizophrenia, 8 with bipolar disorder, 12 with depression, and 11 age- and sex-matched controls. No significant differences were found among the four groups. Our study indicates that the Alzheimer-type changes, which might be related to the likelihood of AD development later in life, are not increased in middle-aged subjects with mental illness. The result also supports the more recent reports that have demonstrated no increased incidence of AD in mentally ill patients.

Diaz-Nido, J., F. Wandosell, et al. (2002). "Glycosaminoglycans and beta-amyloid, prion and tau peptides in neurodegenerative diseases." Peptides 23(7): 1323-32.
Protein aggregation into dense filamentous inclusions is a characteristic feature of many etiologically diverse neurodegenerative disorders including Alzheimer's disease (AD), spongiform encephalopathies, and tauopathies. Thus, beta-amyloid peptide (Abeta) accumulates within senile amyloid plaques in AD, protease-resistant prion protein constitutes the amyloid deposits in spongiform encephalopathies and tau protein gives rise to neurofibrillary tangles (NFT) both in AD and in tauopathies. Curiously, these abnormal protein inclusions contain, in addition to their major peptide components, some associated sulfated glycosaminoglycans (sGAG). Here we discuss the proposal that the binding of sGAG to aggregate-forming peptides may modify the pathogenic process depending on their subcellular localization.

Dudas, B., U. Cornelli, et al. (2002). "Oral and subcutaneous administration of the glycosaminoglycan C3 attenuates Abeta(25-35)-induced abnormal tau protein immunoreactivity in rat brain." Neurobiol Aging 23(1): 97-104.
High molecular weight glycosaminoglycans (GAG) and proteoglycans (PG) affect pathological changes of the brain in Alzheimer's disease (AD). PG stimulate the processing and aggregation of amyloid-beta (Abeta), protect the protein from proteolysis, and increase the formation of neurofibrillary tangles by inducing the hyperphosphorylation of tau protein. These effects may be competitively inhibited by GAG.We have studied the effects of orally (by gavage) and subcutaneously (s.c.) administered low molecular weight heparin, C3 (4-10 oligosaccharides; MW = 2.1 kDa; USP value = 12 U/mg), on abnormal tau-2 protein immunoreactivity in the rat hippocampus following a single, unilateral intra-amygdaloid administration of Abeta(25-35). Oral administration of C3 (25 mg/kg; once daily) was initiated 3 days prior to Abeta(25-35) administration, and was continued daily for an additional 14 days. S.c. administration of C3 (2.5 mg/kg, twice daily), was started 3 days prior to, and was continued for 32 days after, Abeta(25-35) administration. Animal brains were subsequently processed for tau-2, ChAT-immunoreactivity, choline acetyltransferase (ChAT) activity and acetylcholinesterase (AChE) activity. Both oral and s.c. administration of C3 attenuated Abeta(25-35) induced appearance of tau-2-immunoreactive (IR) perikarya in the ipsilateral hippocampus (P < 0.05). Hippocampal cholinergic enzyme activity in C3 treated animals was not significantly different from control animals.The present findings suggest that C3 might be used successfully to prevent abnormal tau protein formation in chronic neurologic diseases, such as AD. Moreover, our data demonstrate that the mechanism of this effect does not appear to influence the cholinergic system of the brain.

Forman, M. S., M. L. Schmidt, et al. (2002). "Tau and alpha-synuclein pathology in amygdala of Parkinsonism-dementia complex patients of Guam." Am J Pathol 160(5): 1725-31.
Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disorder of Chamorro residents of Guam and the Mariana Islands, characterized by abundant neuron loss and tau neurofibrillary pathology similar to that observed in Alzheimer's disease (AD). A variety of neurodegenerative diseases with tau pathology including ALS/PDC also have alpha-synuclein positive pathology, primarily in the amygdala. We further characterized the tau and alpha-synuclein pathology in the amygdala of a large series of 30 Chamorros using immunohistochemical and biochemical techniques. Tau pathology was readily detected in both affected and unaffected Chamorros. In contrast, alpha-synuclein pathology was detected in 37% of patients with PDC but not detected in Chamorros without PDC or AD. The alpha-synuclein aggregates often co-localized within neurons harboring neurofibrillary tangles suggesting a possible interaction between the two proteins. Tau and alpha-synuclein pathology within the amygdala is biochemically similar to that observed in AD and synucleinopathies, respectively. Thus, the amygdala may be selectively vulnerable to developing both tau and alpha-synuclein pathology or tau pathology may predispose it to synuclein aggregation. Furthermore, in PDC, tau and alpha-synuclein pathology occurs independent of beta-amyloid deposition in amygdala thereby implicating the aggregation of these molecules in the severe neurodegeneration frequently observed in this location.

Fukatsu, R., M. Fujii, et al. (2002). "[Psychiatric symptoms and pathological processes in patients with Alzheimer's disease--special reference to dissection analysis of the visual-spatial world]." Seishin Shinkeigaku Zasshi 104(2): 139-43.

Garcia-Jimenez, A., R. F. Cowburn, et al. (2002). "Loss of stimulatory effect of guanosine triphosphate on [(35)S]GTPgammaS binding correlates with Alzheimer's disease neurofibrillary pathology in entorhinal cortex and CA1 hippocampal subfield." J Neurosci Res 67(3): 388-98.
Heterotrimeric guanosine triphosphate (GTP)-binding proteins (G-proteins) couple many different cell surface receptor types to intracellular effector mechanisms. Uncoupling between receptors and G-proteins and between G-proteins and adenylyl cyclase (AC) and phospholipase C (PLC) has been described for Alzheimer's disease (AD) brain. However, there is little information on whether altered G-protein signaling in AD is just an end-stage phenomenon or is important for the progression of disease pathology. Here we used [(35)S]GTPgammaS autoradiography to study G-protein distribution in sections of entorhinal cortex and hippocampus from 23 cases staged for neurofibrillary changes and amyloid deposits according to Braak and Braak (Acta Neuropathol. [1991] 82:239-259). We also studied the effects of GTP, which has been found to increase [(35)S]GTPgammaS binding in an Mg(2+)-dependent manner. Results show that the ability of GTP (3 microM) to stimulate [(35)S]GTPgammaS binding declined significantly with staging for neurofibrillary changes in the entorhinal cortex (P < 0.05, ANOVA) and CA1 subfield of the hippocampus (P < 0.05, ANOVA). No significant changes were seen for [(35)S]GTPgammaS binding in the absence of GTP. Our results suggest a decrease in G-protein GTP hydrolysis, which correlates with the progression of AD neurofibrillary changes, in the regions most affected by this pathology. These alterations appear to occur prior to stages corresponding to clinical disease and could lead to an impaired regulation of several signaling systems in AD brain.

Ghebremedhin, E., D. R. Thal, et al. (2002). "Age-dependent association between butyrylcholinesterase K-variant and Alzheimer disease-related neuropathology in human brains." Neurosci Lett 320(1-2): 25-8.
The association between the K-variant of the butyrylcholinesterase gene (BCHE-K) and Alzheimer disease (AD) or AD-related neuropathology has been reported to date with conflicting results. Here, we determined in a sample of 521 cases the severity of AD-related neuropathology and the polymorphisms of both BCHE-K and apolipoprotein E (ApoE). Histopathologically, all brains were classified according to procedures permitting differentiation of the evolutionary stages of neurofibrillary tangles (NFTs) and amyloid-beta-protein deposition (A beta-deposits). The results show that the association between BCHE-K and AD-related neuropathology only was limited to homozygotes for the K allele (P=0.036 for NFTs, and P=0.045 for A beta-deposits) at ages > or = 70 years but not 50-69 years. Furthermore, no interaction was apparent between BCHE-K and ApoE.

Gordon, M. N., L. A. Holcomb, et al. (2002). "Time course of the development of Alzheimer-like pathology in the doubly transgenic PS1+APP mouse." Exp Neurol 173(2): 183-95.
Doubly transgenic mice expressing both a mutated amyloid precursor protein and a mutated presenilin-1 protein accumulate A(beta) deposits as they age. The early A(beta) deposits were found to be primarily composed of fibrillar A(beta) and resembled compact amyloid plaques. As the mice aged, nonfibrillar A(beta) deposits increased in number and spread to regions not typically associated with amyloid plaques in Alzheimer's disease. The fibrillar, amyloid-containing deposits remained restricted to cortical and hippocampal structures and did not increase substantially beyond the 12-month time point. Even at early time points, the fibrillar deposits were associated with dystrophic neurites and activated astrocytes expressing elevated levels of glial fibrillary acidic protein. Microglia similarly demonstrated increased staining for complement receptor-3 in the vicinity of A(beta) deposits at early time points. However, when MHC-II staining was used to assess the degree of microglial activation, full activation was not detected until mice were 12 months or older. Overall, the regional pattern of A(beta) staining resembles that found in Alzheimer disease; however, a progression from diffuse A(beta) to more compact amyloid deposits is not observed in the mouse model. It is noted that the activation of microglia at 12 months is coincident with the apparent stabilization of fibrillar A(beta) deposits, raising the possibility that activated microglia might clear fibrillar A(beta) deposits at a rate similar to their rate of formation, thereby establishing a relatively steady-state level of amyloid-containing deposits.

Gotz, M. E., M. Wacker, et al. (2002). "Unaltered brain levels of 1,N2-propanodeoxyguanosine adducts of trans-4-hydroxy-2-nonenal in Alzheimer's disease." Neurosci Lett 324(1): 49-52.
In recent years, an important role for the pathogenesis of Alzheimer's disease (AD) has been ascribed to oxidative stress. Trans-4-hydroxy-2-nonenal, a product of lipid peroxidation, forms stable adducts with a variety of nucleophilic substituents such as thiols or amino moieties. Here, we report the quantification of 1,N2-propanodeoxyguanosine adducts of trans-4-hydroxy-2-nonenal (HNE-dGp) using the specific and very sensitive method of 32P-postlabeling of deoxyguanosine adducts derived from nuclear DNA in neuron rich areas of the hippocampus, the parietal cortex, and the cerebellum of postmortem brains from patients with AD and age matched controls. Adduct levels were highest in the hippocampus, followed by the cerebellum and parietal cortex irrespective of the disease. Neither age, postmortem delay time, gender, nor the extent of neurofibrillary deposits affected tissue adduct levels in the brain areas examined. Although distinctively present in the human brain, the level of HNE-dGp adducts appears not to be useful as a biomarker for AD.

Green, E. K., U. Thaker, et al. (2002). "A polymorphism within intron 11 of the tau gene is not increased in frequency in patients with sporadic Alzheimer's disease, nor does it influence the extent of tau pathology in the brain." Neurosci Lett 324(2): 113-6.
There are numerous polymorphisms within the tau gene but these are in complete linkage disequilibrium and exist as two common extended haplotypes H1 and H2. We have investigated the frequency of these haplotypes in 83 cases of sporadic Alzheimer's disease (AD) using the +34 polymorphism in intron 11 of the tau gene as a marker of H1 and H2 haplotypes. The total amount of hyperphosphorylated tau protein (tau load), present as neurofibrillary tangles, neuropil threads or plaque neurites, was quantified in the frontal cortex of these patients and related to tau haplotype. We found no increase in H1H1 haplotype in this autopsy population of cases with AD compared to published control data. Stratification of cases for apolipoprotein E (APO E) genotype showed a slight, but not statistically significant, overrepresentation of epsilon 4 allele amongst bearers of H2 haplotype. There were no overall differences in tau load between haplotype groups though cases within each haplotype group bearing APO E epsilon 4 allele had a significantly higher tau load than those without epsilon 4 allele. Neither age at onset or duration of illness differed according to tau haplotype. We conclude that the frequency of tau gene H1 haplotype is not elevated in AD and possession of this has no impact upon the amount of tau pathology in AD.

Griffin, W. S. and R. E. Mrak (2002). "Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer's disease." J Leukoc Biol 72(2): 233-8.
Interleukin-1 (IL-1), a key molecule in systemic immune responses in health and disease, has analogous roles in the brain where it may contribute to neuronal degeneration. Numerous findings suggest that this is the case. For example, IL-1 overexpression in the brain of Alzheimer patients relates directly to the development and progression of the cardinal neuropathological changes of Alzheimer's disease, i.e., the genesis and accumulation of beta-amyloid (Abeta) plaques and the formation and accumulation of neurofibrillary tangles in neurons, both of which contribute to neuronal dysfunction and demise. Several genetic studies show that inheritance of a specific IL-1A gene polymorphism increases risk for development of Alzheimer's disease by as much as sixfold. Moreover, this increased risk is associated with earlier age of onset of the disease. Homozygosity for this polymorphism in combination with another in the IL-1B gene further increases risk.

Hardy, J. and D. J. Selkoe (2002). "The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics." Science 297(5580): 353-6.
It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid beta-peptide (Abeta) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Abeta in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Abeta production and Abeta clearance.

Harman, D. (2002). "Alzheimer's disease: role of aging in pathogenesis." Ann N Y Acad Sci 959: 384-95; discussion 463-5.
Alzheimer's disease (AD) is characterized by intraneuronal fibrillary tangles, plaques, and cell loss. Brain lesions in both sporadic AD (SAD) and familial AD (FAD) are the same, and in the same distribution pattern, as those in individuals with Down syndrome (DS) and in smaller numbers in nondemented older individuals. Dementia onset is around 40 years for DS, 40-60 years for FAD, and usually over 60 years for SAD. The different categories of AD may be due to processes that augment to different degrees the innate cellular aging rate, that is, mitochondrial superoxide radical (SO) formation. Thus, they increase the rate of accumulation of AD lesions. This lowers the age of onset into the dementia ranges associated with DS, FAD, and SAD, and concomitantly shortens life spans. Faster aging lowers AD onset age by decreasing the onset age for neurofibrillary tangle formation and neuronal loss, and the age when brain intercellular H2O2 can activate microglial cells. The early AD onset in DS is attributed to a defective mitochondrial complex 1. The proteins associated with FAD and their normal counterparts undergo proteolytic processing in the endoplasmic reticulum (ER). The mutated compounds increase the ratio of betaA42 to betaA40 and likely also down-regulate the ER calcium (Ca2+) buffering activity. Decreases in ER Ca2+ content should increase the mitochondrial Ca2+ pool, thus enhancing SO formation. SAD may be due to increased SO formation caused by mutations in the approximately 1000 genes involved in mitochondrial biogenesis and function. The hypothesis suggests measures to prevent and treat.

Head, E., I. Lott, et al. (2002). "beta-Amyloid deposition and neurofibrillary tangle association with caspase activation in Down syndrome." Neurosci Lett 330(1): 99.
Individuals with Down syndrome (DS) and Alzheimer's disease (AD) develop senile plaques, neurofibrillary tangles (NFT), and neuron loss. Recent studies demonstrate the activation of apoptotic pathways in AD; less data is available in DS. The DS brain was examined using immunocytochemistry and antibodies against the active fragment of caspase-8 (AC, 8) and to caspase-3 cleavage products of fodrin (CCP), a neuronal cytoskeleton protein. The hippocampus demonstrated widespread accumulation of fodrin CCP and AC8 in NFTs and dystrophic neurites. Individual neurons contained intracellular beta-amyloid (Abeta) and fodrin CCP providing evidence that caspase activation can occur with both NFT and Abeta. Abeta within or around neurons in addition to contributing to NFT formation may also trigger apoptotic pathways. Caspase activation may lead to the cleavage of critical cellular proteins and neuronal cell death associated with DS.

Hernandez, F., M. Perez, et al. (2002). "Sulfo-glycosaminoglycan content affects PHF-tau solubility and allows the identification of different types of PHFs." Brain Res 935(1-2): 65-72.
Sulfo-glycosaminoglycans (sGAGs) are involved in the assembly of tau in at least a subpopulation of paired helical filaments (PHFs) in Alzheimer's disease (AD). To further understand the role of sGAG molecules in the structure of PHFs, we isolated PHFs from patients with AD and treated them with heparinase. Immunoelectron microscopy and Western blotting (WB) were used later on to analyze the changes obtained. The heparinase treatment abolished Tau14 and AT8 immunodecoration (two N-terminal tau antibodies) and increased PHF-1 labeling (a C-terminal antibody). In addition, heparinase-treated filaments are more labile than control ones as demonstrated by sodium dodecyl sulfate-extraction and subsequent WB. In summary, our results demonstrate that sGAG content affects PHF conformation as well as PHF-tau solubilization.

Hof, P. R. and D. P. Perl (2002). "Neurofibrillary tangles in the primary motor cortex in Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex." Neurosci Lett 328(3): 294-8.
The amyotrophic lateral sclerosis/parkinsonism-dementia complex is a chronic neurodegenerative disorder with high prevalence among the native Chamorro population of Guam. The cortical pathology of the disease is characterized by the widespread occurrence of cortical neurofibrillary tangles that exhibit a specific laminar and regional distribution different from that seen in Alzheimer's disease (AD). In spite of the major motor symptomatology, the degree to which the primary motor cortex is affected in this disease has not been investigated in detail. We report here that the primary motor cortex in Guamanian cases contains high numbers of neurofibrillary tangles, contrasting sharply with the situation in AD and in non-Chamorro cases of amyotrophic lateral sclerosis. Furthermore, the cases with predominant parkinsonism-dementia are more severely affected than amyotrophic lateral sclerosis cases. These data suggest that the regional and cellular pathology of Guamanian cases differs radically from that commonly observed in neurodegenerative diseases outside Guam and point to the existence of subgroups in the spectrum of clinical manifestations seen in Guamanian patients.

Iida, T., A. Furuta, et al. (2002). "Expression of 8-oxoguanine DNA glycosylase is reduced and associated with neurofibrillary tangles in Alzheimer's disease brain." Acta Neuropathol (Berl) 103(1): 20-5.
Recent studies have confirmed the role of reactive oxygen species in the pathogenesis of Alzheimer's disease (AD). 8-Oxo-2'-deoxyguanosine accumulation in AD brain has been discussed, but few studies of DNA repair enzymes in AD brain have been done. Further, a relationship between mitochondrial function and oxidative stress has been noticed. In this study, to evaluate the repair mechanism for oxidative DNA damage in AD brain, we investigated brain tissues from autopsy cases of AD and control cases using an antibody against the mitochondrial form of 8-oxoguanine DNA glycosylase (hOGG1-2a), an enzyme that repairs 8-oxo-2'-deoxyguanosine. hOGGI-2a is expressed mainly in the neuronal cytoplasm in both AD and control cases in regionally different manners. Expression of hOGG1-2a is decreased in the orbitofrontal gyrus and entorhinal cortex in AD compared to that in control cases. Immunoreactivity to hOGG1-2a is associated with neurofibrillary tangles, dystrophic neurites and reactive astrocytes in AD. Our results indicate that the repair enzyme for oxidative damage in mitochondrial DNA may not function appropriately in AD, and thus oxidative DNA damage in mitochondria may be involved in the pathomechanism of AD.

Iivonen, S., M. Hiltunen, et al. (2002). "Seladin-1 transcription is linked to neuronal degeneration in Alzheimer's disease." Neuroscience 113(2): 301-10.
Seladin-1 is a gene recently shown to be down-regulated in brain regions selectively degenerated in Alzheimer's disease. The sequence of seladin-1 shares similarities with flavin-adenine-dinucleotide-dependent oxidoreductases and it has been found to protect cells from apoptotic cell death. In this work, we show that the transcription of seladin-1 is selectively down-regulated in the brain areas affected in Alzheimer's disease. The down-regulation in seladin-1 transcription was associated with hyperphosphorylated tau seen as linkage to immunohistochemically detected paired helical filament tau, neuritic plaques and neurofibrillary tangles. In contrast, no association was found between seladin-1 transcription and beta-amyloid deposition when analyzing human samples or tissue from transgenic animals. Furthermore, the relative transcription of seladin-1 was found to fluctuate during aging in the transgenic mouse model of Alzheimer's disease. The fluctuation was enhanced by Alzheimer's disease causing mutations in presenilin-1 and amyloid precursor protein genes. Finally, seladin-1 transcription was found to be up-regulated in mouse N2a cells induced to undergo apoptosis with okadaic acid.The results presented here indicate that seladin-1 transcription is selectively down-regulated in brain regions vulnerable to Alzheimer's disease and this down-regulation is associated with the hyperphosphorylation of tau protein.

Iqbal, K., C. Alonso Adel, et al. (2002). "Significance and mechanism of Alzheimer neurofibrillary degeneration and therapeutic targets to inhibit this lesion." J Mol Neurosci 19(1-2): 95-9.
Abnormally hyperphosphorylated tau which is the major protein subunit of paired helical filaments (PHF)/neurofibrillary tangles is the pivotal lesion in Alzheimer disease (AD) and related tauopathies. The cosegregation of tau mutations with disease in inherited cases of frontotemporal dementia has confirmed that abnormalities in this protein can be a primary cause of neurodegeneration. Unlike normal tau that promotes assembly and maintains the structure of microtubules, the abnormally hyperphosphorylated protein sequesters normal tau, MAP1 and MAP2 and consequently disassembles microtubules. The abnormal hyperphosphorylation also promotes the self assembly of tau into tangles of PHF. The hyperphosphorylation of tau in AD is probably due to a protein phosphorylation/dephosphorylation imbalance produced by a decrease in the activity of protein phosphatase (PP)-2A and increase in the activities of tau kinases which are directly or indirectly regulated by PP-2A. Two of the most promising pharmacologic therapeutic approaches to AD are (1) the development of drugs that can inhibit the sequestration of normal MAPs by the abnormally hyperphosphorylated tau, and (2) the development of drugs that can reverse the abnormal hyperphosphorylation of tau by correcting the protein phosphorylation/dephosphorylation imbalance.

Ishizawa, K., T. Komori, et al. (2002). "Hyperphosphorylated tau deposition parallels prion protein burden in a case of Gerstmann-Straussler-Scheinker syndrome P102L mutation complicated with dementia." Acta Neuropathol (Berl) 104(4): 342-50.
Hyperphosphorylated tau (p-tau) deposition has been documented in a limited population of patients with Gerstmann-Straussler-Scheinker syndrome (GSS) with particular point mutations of the prion protein (PrP) gene. Although its pathogenesis is only poorly understood, p-tau in GSS is known to be identical to that in Alzheimer's disease (AD). We conducted immunohistochemical and quantitative image studies on the brain from a 44-year-old man with a 7-year history of dementia, diagnosed as having GSS with a point mutation of the PrP gene at codon 102 (GSS102), the commonest mutation in GSS. Severe spongiform degeneration and numerous PrP plaques were disclosed in the cerebral cortices and hippocampus, consistent with the diagnosis. However, rarely described in GSS102, prominent p-tau deposits as pretangles, neurofibrillary tangles and degenerating neurites were demonstrated adjacent to or around PrP plaques. beta-Amyloid protein (Abeta) plaques were generally sparse and appeared invariably to be of a diffuse type. Double-labeling immunohistochemistry yielded co-localization of p-tau with PrP but not with Abeta. Most PrP plaques did not contain Abeta. These results excluded a diagnosis of concomitant AD. Quantitative analysis on a fractional area density of immunoreactive pixels demonstrated that burdens of PrP and p-tau but not Abeta were significantly correlated. These results suggest that p-tau deposition in this GSS102 is secondarily induced by PrP but not by Abeta (secondary tauopathy). Our study also suggests that p-tau deposition might be a more common phenomenon in long-standing GSS.

Jackson, G. R., M. Wiedau-Pazos, et al. (2002). "Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila." Neuron 34(4): 509-19.
Pathologic alterations in the microtubule-associated protein tau have been implicated in a number of neurodegenerative disorders, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD). Here, we show that tau overexpression, in combination with phosphorylation by the Drosophila glycogen synthase kinase-3 (GSK-3) homolog and wingless pathway component (Shaggy), exacerbated neurodegeneration induced by tau overexpression alone, leading to neurofibrillary pathology in the fly. Furthermore, manipulation of other wingless signaling molecules downstream from shaggy demonstrated that components of the Wnt signaling pathway modulate neurodegeneration induced by tau pathology in vivo but suggested that tau phosphorylation by GSK-3beta differs from canonical Wnt effects on beta-catenin stability and TCF activity. The genetic system we have established provides a powerful reagent for identification of novel modifiers of tau-induced neurodegeneration that may serve as future therapeutic targets.

Jordan-Sciutto, K. L., L. M. Malaiyandi, et al. (2002). "Altered distribution of cell cycle transcriptional regulators during Alzheimer disease." J Neuropathol Exp Neurol 61(4): 358-67.
A number of mechanisms have been proposed to contribute to the selective neuronal cell loss observed during Alzheimer disease (AD). These include the formation and accumulation of amyloid-beta (Abeta)-containing plaques, neurofibrillary tangles (NFTs), and inflammatory processes mediated by astrocytes and microglia. Neuronal responses to such insults in AD brain include increased protein levels and immunoreactivity for kinases known to regulate cell cycle progression. One down-stream target of these cell cycle regulatory proteins, the Retinoblastoma susceptibility gene product (pRb), has been shown to exhibit altered expression patterns in AD. Furthermore, in vitro studies have implicated pRb and one of the transcription factors it regulates, E2F1, in Abeta-induced cell death. To further explore the role of these proteins in AD, we examined the distribution of the E2F1 transcription factor and the hyperphosphorylated form of pRb (ppRb), which is unable to bind and regulate E2F activity, in the cortex of patients with AD and in non-demented controls. We observed increased ppRb and E2FI immunoreactivity in AD brain, with ppRb predominately located in the nucleus and E2F1 in the cytoplasm. Although neither of these proteins significantly co-localized with NFTs, both ppRb and E2F1 were found in cells surrounding a subset of Abeta-containing plaques. These results support a role for G1 to S phase cell cycle regulators in AD.

Kalaria, R. N. (2002). "Small vessel disease and Alzheimer's dementia: pathological considerations." Cerebrovasc Dis 13 Suppl 2: 48-52.
Current evidence suggests that the neuropathology of Alzheimer type of dementia comprises more than amyloid plaques and neurofibrillary tangles. At least a third of Alzheimer disease (AD) cases may exhibit significant cerebrovascular pathology, which constitutes distinct small vessel disease (SVD). Cerebral amyloid angiopathy, microvascular degeneration affecting the cerebral endothelium and smooth muscle cells, basal lamina alterations, hyalinosis and fibrosis are often evident in AD. These changes may be accompanied by perivascular denervation that is causal in the cognitive decline of AD. Amyloid beta protein may cause degeneration of both the larger perforating arterial vessels as well as cerebral capillaries, which represent the blood-brain barrier. In addition, macro- and microinfarctions, haemorrhages, lacunes and ischaemic white matter changes are also present in AD. The development of SVD in late-onset AD may engage an interaction of perivascular mediators as well as circulation-derived factors that perturb the brain vasculature. Peripheral vascular disease such as long-standing hypertension, atrial fibrillation, coronary or carotid artery disease and diabetes could further modify the cerebral circulation such that a sustained hypoperfusion or oligaemia is impacted upon the ageing brain.

Kasparova, J. and V. Dolezal (2002). "[beta-Amyloid, cholinergic neurons and Alzheimer's disease]." Cesk Fysiol 51(2): 82-94.
Alzheimer's disease is the most common neurodegenerative disorder in men and its incidence increases with the prolongation of life expectancy. The late phase of the disease is accompanied by a failure of cognitive and mental functions. Post mortem examination of the brain reveals the presence of neuritic plaques and neurofibrillary tangles, particularly in the cortex and hippocampus, and a reduction of the number of cerebrocortical neurons. Biochemical changes include the affliction of various neurotransmitter systems with the obligatory damage of the basal forebrain cholinergic system. Understanding of the pathogeny of Alzheimer's disease and, consequently, of ways to its therapy is still quite limited, in spite of enormous effort by investigators. Advanced molecular biological and genetical approaches indicate that the primary cause of Alzheimer's disease is the accumulation and toxic action of beta-amyloid peptide, which is formed as a less common breakdown product of the amyloid precursor protein. In this review we briefly outline some recent ideas concerning the origin and progression of the disease, with the main focus on the metabolism of beta-amyloid and on possible mechanisms of its deleterious influence on the neuronal, particularly cholinergic cells. Two basic cytotoxic effects of beta-amyloid on neurons appear to be the disturbance of the homeostasis of intracellular calcium ions and the induction of oxidative stress, and they together bring about necrotic or apoptotic cell death. However, it has been found in experiments that the damage of cholinergic neurons and cholinergic neurotransmission can be induced by beta-amyloid at such low concentrations which do not yet evoke general cytotoxic effects. Weakening of cholinergic neurotransmission is known to result in an increase in the production of beta-amyloid, and the damage of cholinergic neurons thus seems to initiate a vicious circle which speeds up the progression of the disease.

Koistinaho, M., M. I. Kettunen, et al. (2002). "Beta-amyloid precursor protein transgenic mice that harbor diffuse A beta deposits but do not form plaques show increased ischemic vulnerability: role of inflammation." Proc Natl Acad Sci U S A 99(3): 1610-5.
beta-amyloid (A beta), derived form the beta-amyloid precursor protein (APP), is important for the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of A beta plaques and neurofibrillary tangles, and loss of neurons. However, introducing a human wild-type or mutant APP gene to rodent models of AD does not result in clear neurodegeneration, suggesting that contributory factors lowering the threshold of neuronal death may be present in AD. Because brain ischemia has recently been recognized to contribute to the pathogenesis of AD, we studied the effect of focal brain ischemia in 8- and 20-month-old mice overexpressing the 751-amino acid isoform of human APP. We found that APP751 mice have higher activity of p38 mitogen-activated protein kinase (p38 MAPK) in microglia, the main immune effector cells within the brain, and increased vulnerability to brain ischemia when compared with age-matched wild-type mice. These characteristics are associated with enhanced microglial activation and inflammation but not with altered regulation of cerebral blood flow, as assessed by MRI and laser Doppler flowmetry. Suppression of inflammation with aspirin or inhibition of p38 MAPK with a selective inhibitor, SD-282, abolishes the increased neuronal vulnerability in APP751 transgenic mice. SD-282 also suppresses the expression of inducible nitric-oxide synthase and the binding activity of activator protein 1. These findings elucidate molecular mechanisms of neuronal injury in AD and suggest that antiinflammatory compounds preventing activation of p38 MAPK in microglia may reduce neuronal vulnerability in AD.

Kotilinek, L. A., B. Bacskai, et al. (2002). "Reversible memory loss in a mouse transgenic model of Alzheimer's disease." J Neurosci 22(15): 6331-5.
Alzheimer's disease (AD) is a neurodegenerative condition, believed to be irreversible, characterized by inexorable deterioration of memory and intellect, with neuronal loss accompanying amyloid plaques and neurofibrillary tangles. In an amyloid precursor protein transgenic mouse model, Tg2576, little or no neuronal loss accompanies age-related memory impairment or the accumulation of Abeta, a 40-42 aa polypeptide found in plaques. Recently, we have shown inverse correlations between brain Abeta and memory in Tg2576 mice stratified by age (Westerman et al., 2002). Broadening the age range examined obscured this relationship, leading us to propose that small, soluble assemblies of Abeta disrupt cognitive function in these mice. Here we show that memory loss can be fully reversed in Tg2576 mice using intraperitoneally administered BAM-10, a monoclonal antibody recognizing the N terminus of Abeta. The beneficial effect of BAM-10 was not associated with a significant Abeta reduction, but instead eliminated the inverse relationship between brain Abeta and memory. We postulate that BAM-10 acts by neutralizing Abeta assemblies in the brain that impair cognitive function. Our results indicate that a substantial portion of memory loss in Tg2576 mice is not permanent. If these Abeta assemblies contribute significantly to memory loss in AD, then successfully targeting them might improve memory in some AD patients.

Kovacs, G. G. and H. Budka (2002). "Aging, the brain and human prion disease." Exp Gerontol 37(4): 603-5.
Human prion diseases (PrD) preferentially manifest in the elderly. Their neuropathology may coexist with tau immunoreactive neuropil threads, neurofibrillary tangles, and beta-amyloid senile plaques, most likely representing an age-related change rather than a pathogenic link with Alzheimer's disease. Cerebrovascular disease with brain infarction, another malady preferring the elderly, is useful to prove the origin of PrD-associated prion protein deposition exclusively from neurons.

Kratzsch, T., J. Peters, et al. (2002). "[Etiology and pathogenesis of Alzheimer dementia]." Wien Med Wochenschr 152(3-4): 72-6.
Alzheimer's disease (AD) is the most common cause of primary dementia, characterized by a progressive process of pathophysiological restructuring of the brain over decades. The hallmark of Alzheimer's disease is the extracellular accumulation and deposition of insoluble amyloid, to be found in the parenchyma in the form of amyloid plaques and in meningeal and cerebral vessels as a congophile angiopathy. Equally conspicuous is the intraneuronal occurrence of neurofibrillary tangles, consisting mainly of hyperphosphorylated tau-protein. Amyloid plaques and neurofibrillary tangles are characteristic, but not specific to Alzheimer's disease. Similar changes can be found in healthy ageing processes and in various other neurodegenerative diseases. It is common to differentiate between an early-onset, familial Alzheimer's disease with an established genetic etiology, representing only about 5% of all cases, and the more typical late-onset, sporadic Alzheimer's disease with an age of onset above 65 years and no clear pattern of inheritance. Although there seems to be a large heterogeneity in the etiology of Alzheimer's disease, the amyloid-cascade-hypothesis has taken a central position as a model for the general etiopathogenesis. The regulation of amyloid plaques underlies a diversity of cellular and molecular factors. In addition to ageing, apolipoprotein E 4 is a firmly established risk factor. Disturbance in the cerebral glucose metabolism, especially in the hippocampal regions, is a further proposed factor in the pathogenesis of Alzheimer's disease. The wide-spread loss of cortical cholinergic neurotransmission associated with the cognitive deficits is of importance to the comprehension of the symptoms and the present pharmacotherapy of Alzheimer's disease.

Kril, J. J., S. Patel, et al. (2002). "Neuron loss from the hippocampus of Alzheimer's disease exceeds extracellular neurofibrillary tangle formation." Acta Neuropathol (Berl) 103(4): 370-6.
Neurofibrillary tangle (NFT) formation in the CA1 region of the hippocampus is one of the early events in the pathogenesis of Alzheimer's disease (AD). As the disease progresses more NFTs form and there is substantial neuron loss. In this study we investigated whether NFT formation accounts for all the CA1 pyramidal neuron loss seen in AD. Using unbiased stereological techniques, we estimated the total number of neurons and the number of intra- and extra-cellular NFTs in the hippocampus of 10 patients with AD and 10 age-matched controls. Marked neuronal loss (approximately 60%) was identified in AD, although NFTs accounted for only a small proportion of this loss (2.2-17.2%, mean 8.1%). Analysis of NFT accumulation with duration of dementia showed a linear relationship, supporting the belief that NFTs progressively accumulate with time.

Kuusisto, E., A. Salminen, et al. (2002). "Early accumulation of p62 in neurofibrillary tangles in Alzheimer's disease: possible role in tangle formation." Neuropathol Appl Neurobiol 28(3): 228-37.
Neurofibrillary tangles (NFTs) and neuritic plaques (NPs) are two major histopathological lesions in Alzheimer's disease (AD). Although their aetiological relationship is unclear, both NFTs and dystrophic neurites of NPs display immunoreactivity for ubiquitin. This suggests that dysfunction in ubiquitin-mediated proteolysis and the resulting accumulation of ubiquitin-conjugated proteins may contribute to the origination of dystrophic neurites and NFTs. We recently discovered a novel constituent of neuropathological protein aggregates, ubiquitin-binding protein p62, with evidence that the accumulation of ubiquitin-conjugated proteins and p62 into cytoplasmic inclusions might be interconnected. In the present work we examined in detail the role of p62 in AD-type pathology, i.e. NFTs, NPs and neuropil threads. Using immunohistochemistry for p62, ubiquitin and hyperphosphorylated tau, we analysed parietal cortical samples of 15 clinicopathologically verified AD cases and nine nondemented aged subjects with abundant NPs. We found that p62 immunoreactivity appears early during neurofibrillary pathogenesis and is invariably and stably present in NFTs. In contrast, p62 was absent or barely detectable in neuropil threads. Furthermore, NP-associated dystrophic neurites were generally devoid of p62, regardless of their content of hyperphosphorylated tau and/or ubiquitin. The results suggest that early involvement of p62 might be critical in the aggregation of hyperphosphorylated tau into perikaryal aggregates, i.e. NFTs.

Lau, L. F., J. B. Schachter, et al. (2002). "Tau protein phosphorylation as a therapeutic target in Alzheimer's disease." Curr Top Med Chem 2(4): 395-415.
Neurofibrillary tangles (NFTs) are a distinguishing neuropathological feature found in postmortem brains of Alzheimer s disease (AD) and tauopathy patients. The density of these lesions correlates with severity of AD and their distribution follows a characteristic pattern of expansion as the disease progresses. The principle components of NFTs are highly phosphorylated forms of the microtubule-associated protein, tau. Tau phosphorylation is believed to initiate or facilitate dissociation from microtubules leading to microtubule destabilization, decay of cellular transport properties, and cell death. This review summarizes recent data and prevailing views on the roles of protein kinases and phosphatases in the regulation of tau phosphorylation in vitro and in vivo, taking into account data from human neurodegenerative diseases and from transgenic rodent models. Small molecule inhibitors of tau phosphorylation that serve as important research tools and possibly the basis of potential new therapeutics, are also described. Key challenges in developing effective therapeutic agents include identification of the relevant kinase(s) responsible for aberrant tau phosphorylation in AD, synthesis of inhibitors selectively targeting those kinases and establishment of appropriate animal models.

Leroy, K., A. Boutajangout, et al. (2002). "The active form of glycogen synthase kinase-3beta is associated with granulovacuolar degeneration in neurons in Alzheimer's disease." Acta Neuropathol (Berl) 103(2): 91-9.
Glycogen synthase kinase-3beta (GSK-3beta) is a physiological kinase for tau and is a candidate protein kinase involved in the hyperphosphorylation of tau present in paired helical filament (PHF)-tau of neurofibrillary tangles (NFT) in Alzheimer's disease (AD). GSK-3beta is also a key element of several signaling cascades (including cell death cascades). We have investigated the immunocytochemical localization of GSK-3 immunoreactivity in AD. Neurons exhibiting strongly GSK-3-immunoreactive granules were observed in AD, with a much higher frequency than in control subjects. This immunoreactivity was found to co-localize with the granulovacuolar degeneration (GVD) and to be associated with the granules of the granulovacuolar bodies. The GVD granules showed a strong GSK-3alpha and GSK-3beta immunoreactivity, and this immunoreactivity was abolished by preabsorption with recombinant GSK-3. In addition, the GVD immunoreactivity was observed with an antibody against the tyrosine-phosphorylated and active form of GSK-3. Some granules of the granulovacuolar degeneration were also intensely labeled with an antibody specific for tau isoforms containing insert 1 (exon 2) and with antibodies specific for tau phosphorylated on Ser262 and for tau phosphorylated on Thr212/Ser214, two phosphorylation sites generated in vitro by GSK-3alpha and beta. GSK-3beta was expressed in neurons containing NFT but only a small proportion of intracellular NFT were observed to be GSK-3beta immunoreactive. Immunoblotting analysis of fractions enriched in PHF-tau did not reveal any GSK-3beta immunoreactivity in these fractions, indicating that GSK-3beta was only loosely associated to NFT. These results suggest that neurons developing GVD sequester an active, potentially deleterious, form of GSK-3 in this compartment and that increased GSK-3 immunoreactivity in a subset of neurons quantitatively differentiates normal aging from AD.

Liu, F., T. Zaidi, et al. (2002). "Role of glycosylation in hyperphosphorylation of tau in Alzheimer's disease." FEBS Lett 512(1-3): 101-6.
In Alzheimer's disease (AD) brain, microtubule-associated protein tau is abnormally modified by hyperphosphorylation and glycosylation, and is aggregated as neurofibrillary tangles of paired helical filaments. To investigate the role of tau glycosylation in neurofibrillary pathology, we isolated various pools of tau protein from AD brain which represent different stages of tau pathology. We found that the non-hyperphosphorylated tau from AD brain but not normal brain tau was glycosylated. Monosaccharide composition analyses and specific lectin blots suggested that the tau in AD brain was glycosylated mainly through N-linkage. In vitro phosphorylation indicated that the glycosylated tau was a better substrate for cAMP-dependent protein kinase than the deglycosylated tau. These results suggest that the glycosylation of tau is an early abnormality that can facilitate the subsequent abnormal hyperphosphorylation of tau in AD brain.

Ljungberg, M. C., R. Dayanandan, et al. (2002). "Truncated apoE forms tangle-like structures in a neuronal cell line." Neuroreport 13(6): 867-70.
Apolipoprotein E is the predominant brain lipoprotein and polymorphic variation in the APOE gene the major genetic susceptibly factor for late onset Alzheimer's disease (AD). Recently it was reported that carboxyl-truncated ApoE fragments induce tangle-like structures in neurons. We confirm the finding: in mouse neuroblastoma cells truncated apoE fragments lacking the carboxyterminus induce structures that have the appearance of neurofibrillary tangles. However these tangles are not induced in non-neuronal cells even in the presence of co-expressed neurofilaments or tau. Further understanding of the basis of this cell specificity might add to understanding of the cell specificity of tangles in AD.

Lleo, A., M. J. Rey, et al. (2002). "[Asymmetric myoclonic parietal syndrome in a patient with Alzheimer's disease mimicking corticobasal degeneration]." Neurologia 17(4): 223-6.
We describe a patient who presented a progressive asymmetrical parietal syndrome including ideomotor apraxia, hemiinattention, unilateral limb dystonia and myoclonus. The clinical picture of this patient supported the clinical diagnosis of corticobasal degeneration (CBD). However, the neuropathologic examination revealed abundant cortical betaA4-amyloid deposits, and phosphorylated tau accumulation in neuritic plaques, neurofibrillary tangles and neuropil threads corresponding to Alzheimer's disease (AD) stage V of Braak and Braak. This case supports the clinical heterogeneity in AD and the existence of a clinical overlap between AD and CBD.

Lovell, M. A., J. D. Robertson, et al. (2002). "Use of bomb pulse carbon-14 to age senile plaques and neurofibrillary tangles in Alzheimer's disease." Neurobiol Aging 23(2): 179-86.
The time course of formation of neurofibrillary tangles (NFT) and senile plaques (SP) in Alzheimer's disease (AD) brain is unknown. Above ground nuclear weapons testing in the late 1950s and early 1960s led to significantly increased levels of 14C in the atmosphere and carbon cycle. Because the amyloid beta peptide of SP and paired helical filaments of NFT, once formed, are relatively resistant to degradation, 14C levels observed in SP and NFT should reflect their year of formation. The purpose of this study was to develop a method to determine whether 14C levels could be used to define NFT and SP ages. Using accelerator mass spectrometry to measure bomb-pulse 14C levels, we determined the average age of formation of isolated SP and NFT fractions in bulk brain samples of 6 AD subjects. Although preliminary, the results demonstrate that it is possible to use bomb pulse 14C to determine the average year of formation of NFT and SP in the brain in AD. In addition, the data show that these structures, once formed, have a much slower carbon turnover rate than normal brain and are not in a formation/enzymatic degradation equilibrium.

Manabe, T., T. Katayama, et al. (2002). "The cytosolic inclusion bodies that consist of splice variants that lack exon 5 of the presenilin-2 gene differ obviously from Hirano bodies observed in the brain from sporadic cases of Alzheimer's disease patients." Neurosci Lett 328(2): 198-200.
Alzheimer's disease (AD) is a neurodegenerative disorder having several pathological characteristics, namely senile plaques and neurofibrillary tangles. Further, Hirano bodies (HBs), which are stained by hematoxylin-eosin, are also observed in the AD brain. Recently, we reported that an alternative splice variant that lacked exon 5 of the presenilin-2 (PS2) gene (PS2V) was expressed in sporadic AD (SAD) brains, and the PS2V-encoding proteins actually existed in these brains. Furthermore, electron microscopic experiments demonstrated that the PS2V proteins form cytosolic inclusion bodies in the pyramidal cells. In this report, we found that the PS2V-composed inclusion bodies differed obviously from the HBs. This observation suggests the possibility that PS2V-composed inclusions are a novel inclusion body, compared with other pathological characteristics previously reported in the SAD brain. We named this inclusion body the 'PS2V body'.

Mattila, P., T. Togo, et al. (2002). "The subthalamic nucleus has neurofibrillary tangles in argyrophilic grain disease and advanced Alzheimer's disease." Neurosci Lett 320(1-2): 81-5.
Neurofibrillary tangles (NFT) are present in the subthalamic nucleus (STN) of progressive supranuclear palsy and corticobasal degeneration, two sporadic tauopathies with preferential accumulation of tau with four repeats in the microtubule binding domain (4R tau). Since recent evidence suggests that argyrophilic grain disease (AGD) is also a 4R tauopathy, we hypothesized that the STN may also be affected in AGD. Tau immunostaining was used to evaluate NFT in the STN in 18 cases of AGD compared with 18 non-AGD cases matched for age, sex and Braak stage. AGD cases had significantly more NFT in the STN than non-AGD cases (P=0.008) with no relationship between NFT score and Braak stage. Surprisingly, NFT were also found in the STN of some non-AGD cases, notably in cases with advanced Braak stage (i.e. Alzheimer's disease). When AGD and non-AGD were considered as a whole there was a correlation between neurofibrillary degeneration in the STN and Braak stage. This study demonstrates that neurofibrillary degeneration is frequent in the STN in AGD, but also detected in non-AGD cases with advanced Braak stage.

Maurizi, C. P. (2002). "Postencephalitic Parkinson's disease, amyotrophic lateral sclerosis on Guam and influenza revisited: focusing on neurofibrillary tangles and the trail of tau." Med Hypotheses 58(3): 198-202.
Circumstantial evidence links neuropathological changes in postencephalitic Parkinson's disease and amyotrophic lateral sclerosis on Guam to the 1918 influenza pandemic. Postencephalitic Parkinson's disease and amyotrophic lateral sclerosis have neuronal neurofibrillary tangles that anatomically correlate with clinical signs and symptoms. Occurrences of the disorders peaked in the early 1950s and are now disappearing. Neurovirulent influenza associated with the lethal 1918 pandemic is suggested as the etiology of both diseases. Permissive tissue antigens are considered an important contributing factor. Neurofibrillary tangles also correlate with signs and symptoms in Alzheimer's disease. Oxidative stress may be the pathological process that induces neurofibrillary tangles. Tangles contain abnormally phosphorylated tau. In Alzheimer's disease, tau is present in cerebrospinal fluid and is deposited in corpora amylacea, demonstrating the direction of cerebrospinal fluid flow.

Messer, W. S., Jr. (2002). "The utility of muscarinic agonists in the treatment of Alzheimer's disease." J Mol Neurosci 19(1-2): 187-93.
Alzheimer's disease is a progressive neurological disorder characterized by amyloid plaques and neurofibrillary tangles along with memory and cognitive deficits associated with a loss of basal forebrain cholinergic neurons. Efforts to treat Alzheimer's disease have focused on compounds that elevate cholinergic activity such as cholinesterase inhibitors and direct acting muscarinic and nicotinic agonists. Low efficacy and poor selectivity of available compounds have limited the clinical utility of muscarinic agonists. Recent studies suggesting a role for muscarinic agonists in regulating the production of A beta raise the possibility that selective M1 agonists could be useful in treating not only the symptoms, but also the underlying cause(s) of Alzheimer's disease. Thus, renewed efforts have focused on the development of compounds with improved selectivity for M1 receptors and lower toxicity. 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine (CDD-0102) is a potent M1 agonist with a low side effect profile that enhances memory function in animal models of Alzheimer's disease. The available preclinical data suggest that CDD-0102 may be useful in the treatment of Alzheimer's disease.

Mitchell, T. W., E. J. Mufson, et al. (2002). "Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer's disease." Ann Neurol 51(2): 182-9.
Abnormally phosphorylated tau accumulates as neurofibrillary tangles and neuropil threads in older persons with and without Alzheimer's disease. The relationship between neurofibrillary tangles and neuropil threads and how they relate to cognitive function is unknown. This study investigated the relationship between phosphorylated tau lesions and cognitive function in 31 persons participating in the Religious Orders Study, a prospective, longitudinal clinicopathological study of aging and Alzheimer's disease. All subjects underwent detailed neuropsychological performance testing within a year of death and evidenced a spectrum of cognitive performance ranging from normal abilities to mild dementia. Measures of neurofibrillary tangle density and phosphorylated tau immunoreactive structures (predominantly neuropil threads) in the entorhinal and perirhinal cortices by quantitative image analysis were significantly correlated (r = 0.5). In multiple linear regression analyses controlling for age, sex, and education, parahippocampal neurofibrillary tangles and neuropil threads were significantly lower in persons without cognitive impairment compared to those with mild cognitive impairment and/or Alzheimer's disease. Further, neurofibrillary tangles were significantly correlated to measures of episodic memory but not other cognitive abilities; neuropil tangles were not significantly related to memory or other cognitive functions. These data indicate that phosphorylated tau pathology in the ventromedial temporal lobe develop prior to the onset of clinical dementia and their presence is associated with cognitive impairment, particularly impairment of episodic memory.

Muchowski, P. J. (2002). "Protein misfolding, amyloid formation, and neurodegeneration: a critical role for molecular chaperones?" Neuron 35(1): 9-12.
The most conspicuous feature of many neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease, is the occurrence of protein aggregates in ordered fibrillar structures known as amyloid found inside and outside of brain cells. The appearance of aggregates in diseased brains implies an underlying incapacity in the cellular machinery of molecular chaperones that normally functions to prevent the accumulation of misfolded proteins. Here we review recent studies that have revealed a critical role for molecular chaperones in several neurodegenerative disorders.

Mudher, A. and S. Lovestone (2002). "Alzheimer's disease-do tauists and baptists finally shake hands?" Trends Neurosci 25(1): 22-6.
The amyloid cascade hypothesis has been the predominant model of molecular pathogenesis in Alzheimer's disease. The finding of tau mutations in other dementias has added weight to the hypothesis as it suggests that tau-pathology is a downstream but essential part of the dementing process. However, some observations remain difficult to reconcile with the hypothesis. In transgenic mice, for example, amyloid generation does not induce the predicted cascade and in man, plaques and tangles are separated temporally and spatially. One alternative possibility is that some common factor, loss of wnt signalling for example, might induce both plaques and tangles.

Myhre, A. and O. B. Tysnes (2002). "[Etiology and genetics of Alzheimer disease]." Tidsskr Nor Laegeforen 122(1): 50-3.
BACKGROUND: Alzheimer's disease (AD) constitutes more than 50% of all dementias. The diagnosis is mainly based on clinical criteria and a definitive diagnosis of AD is made post-mortem with identification of amyloid plaques and neurofibrillary tangles. A small proportion of the patients are under the age of 60 at diagnosis, known as early-onset AD, and most of these cases have an evident genetic component. Aging is the most important risk factor for developing late-onset AD, but also genetic polymorphisms and many environmental conditions play a part in the development of this multifactorial disease. METHODS: The Medline database was searched for "Alzheimer's and genetics". Histologic data were kindly provided from our hospital's department of pathology. RESULTS AND INTERPRETATION: We consider most of the proved etiological factors, especially the three genetic loci which have been shown to be associated with early-onset AD: amyloid precursor protein (APP) gene, presenilin (PS)-1 and PS-2 genes. Mutations in the PS-1 gene at chromosome 14 are by far the most frequent genetic cause of AD. However, the large number of mutations makes genetic screening difficult. We also discuss the impact of the different ApoE alleles in developing late-onset AD, in addition to other mutations and polymorphisms.

Narita, K., T. Murata, et al. (2002). "A case of diffuse neurofibrillary tangles with calcification." Psychiatry Clin Neurosci 56(1): 117-20.
We report a 79-year-old female with atypical senile dementia with Fahr-type calcification. The patient started to show memory disturbance at the age of 75 years, followed by visual hallucination, stereotypy, personality changes such as irritability, aggression and disinhibition. Brain computed tomography (CT) demonstrated bilateral and symmetric calcification of the basal ganglia and thalamus. Magnetic resonance imaging (MRI) revealed diffuse cortical atrophy pronounced in the fronto-temporal areas. On MRI T1-weighted images the calcified areas showed a mixture of low- and high-intensity signals. Based on the overlapping clinical symptoms of Alzheimer's disease and Pick's disease, together with the brain CT and MRI findings, we clinically diagnosed the patient as having 'diffuse neurofibrillary tangles with calcification' (DNTC). The characteristics of psychiatric symptoms and neuroradiological findings in DNTC are discussed.

Nordberg, A., E. Hellstrom-Lindahl, et al. (2002). "Chronic nicotine treatment reduces beta-amyloidosis in the brain of a mouse model of Alzheimer's disease (APPsw)." J Neurochem 81(3): 655-8.
Alzheimer's disease neuropathology is characterised by beta-amyloid plaques and neurofibrillary tangles. Inhibition of beta-amyloid accumulation may be essential for effective therapy in Alzheimer's disease. In this study we have treated transgenic mice carrying the Swedish mutation of human amyloid precursor protein [Tg(Hu.APP695.K670N-M671L)2576], which develop brain beta-amyloid deposits, with nicotine in drinking fluid (200 microg/mL) from 9-14.5 months of age (5.5 months). A significant reduction in amyloid beta peptide 1-42 positive plaques by more than 80% (p < 0.03) was observed in the brains of nicotine treated compared to sucrose treated transgenic mice. In addition, there was a selective reduction in extractable amyloid beta peptides in nicotine treated mice; cortical insoluble 1-40 and 1-42 peptide levels were lower by 48 and 60%, respectively (p < 0.005), whilst there was no significant change in soluble 1-40 or 1-42 levels. The expression of glial fibrillary acidic protein was not affected by nicotine treatment. These results indicate that nicotine may effectively reduce amyloid beta peptide aggregation in brain and that nicotinic drug treatment may be a novel protective therapy in Alzheimer's disease.

Ohm, T. G., S. Munch, et al. (2002). "Transneuronally altered dendritic processing of tangle-free neurons in Alzheimer's disease." Acta Neuropathol (Berl) 103(5): 437-43.
In Alzheimer's disease (AD), changes in dendritic morphology can be regarded as a result of an inherent disease-specific process associated with the formation of neurofibrillary tangles. Using three-dimensional morphometrical techniques and neuropatholologically staged tissue (Braak classification) of 32 cases, we demonstrate alterations in the dendritic length, branch order and number of segments of a tangle-free neuronal population in the AD-afflicted hippocampus, i.e. parvalbumin-containing cells of the fascia dentata. These alterations occurred primarily on the apical dendritic tree, the target of the entorhinal input. Mean of relative dendritic length, branch order and number of dendritic segments of apical dendrites decreased significantly, by 40-70% comparing stage V to stages 0 or I. In contrast, basal dendrites receiving no entorhinal input did not show significant changes. Entorhinal neurons projecting to the hippocampus are the first to be affected in AD and the first to die, resulting in hippocampal deafferentation. Therefore, this input-specific dendritic alteration of tangle-free neurons suggests that AD is confounded with a transneuronal component resulting from deafferentation. Experiments showed that deafferentation results in altered dendritic geometry causing an impaired signal integration. Thus, transneuronally altered dendritic signal integration might occur in neurons devoid of the major intraneuronal hallmark of AD, i.e. the neurofibrillary tangle.

Panayi, A. E., N. M. Spyrou, et al. (2002). "Determination of cadmium and zinc in Alzheimer's brain tissue using inductively coupled plasma mass spectrometry." J Neurol Sci 195(1): 1-10.
In this work, brain tissue was taken from Alzheimer's Disease (AD) subjects (n=11), 'normal' subjects (n=10) and from subjects with senile involutive cortical changes (SICC) (n=6). Concentrations of Cd and Zn were determined in all samples, using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The brain tissue was selected and obtained from the Netherlands Brain Bank. Samples were taken in each case, from both hemispheres of the superior frontal gyrus, the superior parietal gyrus, the medial temporal gyrus, the hippocampus and the thalamus of the same brain.Cd which is known to have no essential role in the brain was found to follow, as expected, a lognormal distribution of concentrations in 'normal' subjects (Shapiro-Wilk's test (0.98) (p<0.18)). For the Alzheimer's Disease subjects and SICC subjects, the data tends to follow a lognormal distribution, rather than a normal distribution, but is still significantly different from it (Shapiro-Wilk's test (0.97) (p<0.03); (0.93) (p<0.0067), respectively)).In the case of Zn concentrations, the data tends to follow a normal distribution for the 'normal' subject group, even though the data is significantly different from it (Shapiro-Wilk's test (0.95) (p<0.001)). Whereas in the Alzheimer's Disease and SICC subject groups, the data follows a normal distribution (Shapiro-Wilk's test (0.98) (p<0.21); (0.97) (p<0.2002), respectively)).When comparing age-matched groups, for all regions and both hemispheres, no significant differences (p>0.1) for Cd were found between 'normals' and Alzheimer's Disease subjects and Alzheimer's Disease subjects and SICC but at a low level of significance, lower concentrations of Cd were found in the SICC group compared to the 'normals'. For all regions and both hemispheres, Zn was found to be significantly decreased in the Alzheimer's Disease group, compared to the 'normal' and SICC groups. Zn concentrations were also found to be significantly decreased in the 'normals' compared to the SICC group.It is also of interest that Cd negatively correlates with the scale of tangles in both 'normals' (p<0.001) and Alzheimer's Disease subjects (p<0.01). In the SICC subjects Cd correlates negatively with the tangles but not significantly so (p>0.1).

Pei, J. J., H. Braak, et al. (2002). "Up-regulation of cell division cycle (cdc) 2 kinase in neurons with early stage Alzheimer's disease neurofibrillary degeneration." Acta Neuropathol (Berl) 104(4): 369-76.
The major component of Alzheimer's disease (AD) neurofibrillary tangles (NFTs) is abnormally hyperphosphorylated tau aggregated as paired helical filaments (PHFs). Cell division cycle (cdc) 2 kinase is one of the main candidate kinases that phosphorylates normal tau in vitro at several sites seen in PHF-tau. Using brains staged according to Braak and Braak criteria, we investigated the role of cdc2 in neurofibrillary changes in the hippocampal formation, and the entorhinal and temporal cortices. Neurons with tangle-like inclusions positive for active cdc2 were found to appear first in the Pre-alpha layer of the entorhinal cortex, and then extend to other brain regions co-incident with the progressive sequence of neurofibrillary changes. This predictable progressive pattern is not associated with amyloid. The intraneuronal accumulation of active cdc2 appeared to precede the deposition of PHF-tau phosphorylated at Ser 202/Thr 205 sites. These data are consistent with the notion that cdc2 might be involved in the abnormal hyperphosphorylation of tau and consequently aggregation of tau into PHF at an early stage and that increased cdc2 activity is not consequent to the deposition of beta-amyloid in AD brain.

Peila, R., B. L. Rodriguez, et al. (2002). "Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study." Diabetes 51(4): 1256-62.
Type 2 diabetes may be a risk factor for dementia, but the associated pathological mechanisms remains unclear. We evaluated the association of diabetes alone or combined with the apolipoprotein E (APOE) gene with incident dementia and neuropathological outcomes in a population-based cohort of 2,574 Japanese-American men enrolled in the Honolulu-Asia Aging Study, including 216 subjects who underwent autopsy. Type 2 diabetes was ascertained by interview and direct glucose testing. Dementia was assessed in 1991 and 1994 by clinical examination and magnetic resonance imaging and was diagnosed according to international guidelines. Logistic regression was used to assess the RR of developing dementia, and log-linear regression was used to estimate the incident rate ratio (IRR) of neuropathological outcomes. Diabetes was associated with total dementia (RR 1.5 [95% CI 1.01-2.2]), Alzheimer's disease (AD; 1.8 [1.1-2.9]), and vascular dementia (VsD; 2.3 [1.1-5.0]). Individuals with both type 2 diabetes and the APOE epsilon4 allele had an RR of 5.5 (CI 2.2-13.7) for AD compared with those with neither risk factor. Participants with type 2 diabetes and the epsilon4 allele had a higher number of hippocampal neuritic plaques (IRR 3.0 [CI 1.2-7.3]) and neurofibrillary tangles in the cortex (IRR 3.5 [1.6-7.5]) and hippocampus (IRR 2.5 [1.5-3.7]), and they had a higher risk of cerebral amyloid angiopathy (RR 6.6, 1.5-29.6). Type 2 diabetes is a risk factor for AD and VsD. The association between diabetes and AD is particularly strong among carriers of the APOE epsilon4 allele. The neuropathological data are consistent with the clinical results.

Pickering-Brown, S. M., A. M. Richardson, et al. (2002). "Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene." Brain 125(Pt 4): 732-51.
Genetic screening of 171 patients with frontotemporal lobar degeneration disclosed 14 patients, across nine pedigrees, with mutations in the intron to exon 10 in the tau gene, a region regulating the splicing of exon 10 via a stem loop mechanism. Thirteen of these patients had the +16 splice site mutation and one had the +13 splice site mutation. Affected members of all nine families presented with changes in behaviour and social conduct that were prototypical of frontotemporal dementia (FTD). In all patients with the +16 splice site mutation, the behavioural profile was characterized by disinhibition, restless overactivity, a fatuous affect, puerile behaviour and verbal and motor stereotypies. The single patient with the +13 mutation presented a contrasting picture of apathy and inertia. In addition, all patients had evidence of semantic loss. Pathologically, five of the six patients so far autopsied shared frontotemporal atrophy with involvement of the substantia nigra. The underlying histology was that of microvacuolar-type cortical degeneration with a few swollen cells. Tau pathology was widespread throughout the brain and present in neurones and glial cells, mostly in the frontal and temporal cortical regions. This was in the form of neurofibrillary tangles and amorphous tau deposits (pre-tangles); Pick bodies were not observed. Ultrastructurally, the tau filaments had a twisted, ribbon-like morphology distinct from the paired helical filaments of Alzheimer's disease. One patient died from an unrelated illness whilst in the early clinical stages of FTD. In this patient, cortical microvacuolar and astrocytic changes were absent, though there were scattered neurones and glial cells, immunoreactive to tau, throughout the cortical and subcortical regions. The disease process underlying the neurodegeneration within these inherited forms of FTD may therefore stem directly from early, primary alterations in the function of tau. All eight families with the +16 mutation seem to be part of a common extended pedigree, possibly originating from a founder member residing within the North Wales region of Great Britain.

Pirskanen, M., M. Hiltunen, et al. (2002). "Interleukin 1 alpha gene polymorphism as a susceptibility factor in Alzheimer's disease and its influence on the extent of histopathological hallmark lesions of Alzheimer's disease." Dement Geriatr Cogn Disord 14(3): 123-7.
We investigated the association of the interleukin 1alpha (IL1A) (-889) C/T polymorphism with Alzheimer's disease (AD) and with the extent of AD histopathological lesions, the senile/neuritic plaques (SPs/NPs) and neurofibrillary tangles. We evaluated 98 neuropathologically confirmed AD patients and 240 controls as well as 146 clinically diagnosed AD patients and 278 controls but found no association of the IL1A C/T polymorphism with AD even after adjustment for the apolipoprotein E (APOE) genotype, gender or age. The extents of AD histopathological lesions were not influenced by the IL1A genotype except after exclusion of the APOE epsilon4 allele, when a trend towards more SPs/NPs was observed in AD patients with the IL1A C/C compared to patients with the T/T genotype. These results do not confirm previous studies which have indicated that the IL1A C/T polymorphism is a susceptibility factor for AD. However, the IL1A C/C genotype might be associated with the progression of SPs/NPs in AD patients, but the effect is weak and obscured by the APOE epsilon4 allele.

Pratico, D. (2002). "Alzheimer's disease and oxygen radicals: new insights." Biochem Pharmacol 63(4): 563-7.
Alzheimer's disease (AD) is the most common form of neurodegenerative disease, with dementia, in the elderly. In addition to the presence of senile plaques and neurofibrillary tangles, the AD brain exhibits evidence for oxygen radical-mediated damage, a situation commonly known as oxidative stress. However, the ability to directly implicate this mechanism in AD has been a difficult task for several reasons. First, most of the analytical approaches used to investigate oxidative stress turned out to be unreliable. Second, the majority of the published studies have been performed in post-mortem tissues with advanced disease, leaving open the question as to whether oxidative stress is an early event or a common final step secondary to the degenerative process. The discovery of the isoprostanes, recent studies performed in living patients, and the development of transgenic animal models of AD-amyloidosis are three important factors that are helping us to better understand and define the role that oxygen radicals might play in AD pathogenesis. Here we review some of the most recent works that have supported the importance of oxygen radical-mediated damage in AD. The accumulated information points toward an earlier involvement than previously thought of oxidative stress in the pathogenesis of the disease, making this a potential target for therapeutic intervention, especially in subjects at high risk for developing AD.

Probst, A. and M. Tolnay (2002). "[Argyrophilic grain disease (AgD), a frequent and largely underestimated cause of dementia in old patients]." Rev Neurol (Paris) 158(2): 155-65.
Argyrophilic grain disease (AgD) is a late-onset dementia morphologically characterized by abundant neuropil grains (ArGs). ArGs are mainly found in the CA1 subfield of the cornu ammonis, entorhinal and transentorhinal cortices, the amygdala and the hypothalamic lateral tuberal nuclei. We have recently shown that abnormally phosphosphorylated tau protein is the main protein constituent of ArGs and that tau is hyperphosphorylated in up to 80p.100 of nerve cels in areas rich in ArGs. We could demonstrate that at least a subset of grains are formed within dendrites and dendritic side-branches of neurons containing hyperphosphylated tau. Morphology of dendrites containing grains suggests that a process of progressive dendritic shrinkage is taking place in neurons bearing ArGs. Furthermore it became apparent that the presence of ArGs is not necessarily associated with a cognitive decline. Our studies on AgD cases with and without dementia suggest that AgD is a progressive neurodegenerative disorder with early subclinical lesions in anterior part of the hippocampal formation. At later stages involvement of more caudal parts of the hippocampal formation generally results in a cognitive decline. Thus, one possible explanation for the dementia observed in some subjects with AgD is that there is a more widepread loss of postsynaptic structures, including synaptic contacts, throughout the hippocampus-entorhinal/parahippocampal complex and the amygdaloid nuclei. Most of the reported AgD cases are associated with neurofibrillary lesions (e.g. neurofibrillary tangles) which are also typical of Alzheimer's disease (AD). However, neurofibrillary changes do not exceed early (entorhinal and limbic) Braak stages which generally are not associated with a cognitive decline. Additional neuropathological features of AgD include oligodendroglial tau filamentous inclusions ( coiled bodies ), ballooned neurons and astrocytic tau pathology. The clinical features of AgD are poorly understood. However, preliminary data from retrospective studies suggest that in AgD behavioural disturbances will precede memory failure and memory decline. Furthermore, it has been shown that the ApoEe4 allele does not constitute a risk factor for the development of AgD. In conclusion it seems very likely that AgD is a distinct dementing disorder of old age that has to be distinguished from other tauopathies, e.g. AD, by both morphological and genetic criteria.

Rapoport, M., H. N. Dawson, et al. (2002). "Tau is essential to beta -amyloid-induced neurotoxicity." Proc Natl Acad Sci U S A 99(9): 6364-9.
Senile plaques and neurofibrillary tangles, the two hallmark lesions of Alzheimer's disease, are the results of the pathological deposition of proteins normally present throughout the brain. Senile plaques are extracellular deposits of fibrillar beta-amyloid peptide (Abeta); neurofibrillary tangles represent intracellular bundles of self-assembled hyperphosphorylated tau proteins. Although these two lesions are often present in the same brain areas, a mechanistic link between them has yet to be established. In the present study, we analyzed whether tau plays a key role in fibrillar Abeta-induced neurite degeneration in central neurons. Cultured hippocampal neurons obtained from wild-type, tau knockout, and human tau transgenic mice were treated with fibrillar Abeta. Morphological analysis indicated that neurons expressing either mouse or human tau proteins degenerated in the presence of Abeta. On the other hand, tau-depleted neurons showed no signs of degeneration in the presence of Abeta. These results provide direct evidence supporting a key role for tau in the mechanisms leading to Abeta-induced neurodegeneration in the central nervous system. In addition, the analysis of the composition of the cytoskeleton of tau-depleted neurons suggested that the formation of more dynamic microtubules might confer resistance to Abeta-mediated neurodegeneration.

Richardson, J. A. and D. K. Burns (2002). "Mouse models of Alzheimer's disease: a quest for plaques and tangles." Ilar J 43(2): 89-99.
Many genetically altered mice have been designed to help understand the role of specific gene mutations in the pathogenesis of Alzheimer's disease (AD) based on the realization that specific mutations in the genes for amyloid precursor protein--the presenilins and tau--are associated with early-onset familial AD or, in the case of tau mutations, other neurodegenerative diseases with neurofibrillary tangles. However, attempts to reproduce the neuropathology of AD in the mouse have been frustrating. Transgenic designs emphasizing amyloid precursor protein produced mice that develop amyloid plaques, but neurodegeneration and neurofibrillary tangles failed to form. Strategies emphasizing tau resulted in increased phosphorylation of tau and tangle formation, although amyloid plaques were absent. Nevertheless, crossing transgenic animals expressing mutated tau and amyloid precursor protein has produced a mouse that closely recapitulates the neuropathology of AD. A review of the various murine models, their role in understanding the pathogenesis of AD and their use in testing therapeutic regimens, is provided.

Riley, K. P., D. A. Snowdon, et al. (2002). "Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study." Ann Neurol 51(5): 567-77.
The development of interventions designed to delay the onset of dementia highlights the need to determine the neuropathologic characteristics of individuals whose cognitive function ranges from intact to demented, including those with mild cognitive impairments. We used the Braak method of staging Alzheimer's disease pathology in 130 women ages 76-102 years who were participants in the Nun Study, a longitudinal study of aging and Alzheimer's disease. All participants had complete autopsy data and were free from neuropathologic conditions other than Alzheimer's disease lesions that could affect cognitive function. Findings showed a strong relationship between Braak stage and cognitive state. The presence of memory impairment was associated with more severe Alzheimer's disease pathology and higher incidence of conversion to dementia in the groups classified as having mild or global cognitive impairments. In addition to Braak stage, atrophy of the neocortex was significantly related to the presence of dementia. Our data indicate that Alzheimer's neurofibrillary pathology is one of the neuropathologic substrates of mild cognitive impairments. Additional studies are needed to help explain the variability in neuropathologic findings seen in individuals whose cognitive performance falls between intact function and dementia.

Rossler, M., R. Zarski, et al. (2002). "Stage-dependent and sector-specific neuronal loss in hippocampus during Alzheimer's disease." Acta Neuropathol (Berl) 103(4): 363-9.
Recent stereological studies documented a severe loss of hippocampal neurons in end-stage Alzheimer's disease. The development of the disease, however, is progressive and slow, over clinically inconspicuous decades. The Braak-staging system distinguishes six histopathological stages some of which are not accompanied by clinical symptoms. We analyzed hippocampal cell loss in correlation to Braak stages. Neuron numbers were determined with unbiased stereological principles in a defined subportion of the hippocampus of 28 subjects. There were no age-dependent neuronal losses in any of the hippocampal subdivisions examined. Compared to stage I, pyramidal cell loss in CA1 was reduced by 33% in stage IV ( P<0.02) and by 51% in stage V ( P<0.0002). In the subiculum, considerable neuron loss was seen only in stage V (22%; P<0.09). Other subdivisions of the Ammon's horn showed no neuron loss. Neuron loss was greater than volume loss, e.g., neuron loss of 51% between stages I and V in CA1 was accompanied by volume loss of only 25%. Our findings indicate (i) that neuronal loss is sector and stage dependent, (ii) that neuronal loss in CA1 and the subiculum is related to the formation of neurofibrillary tangles, and (iii) that neuron loss makes a weak contribution to the observed volume loss.

Russ, C., S. Lovestone, et al. (2002). "Identification of genomic organisation, sequence variants and analysis of the role of the human dishevelled 1 gene in late onset Alzheimer's disease." Mol Psychiatry 7(1): 104-9.
Alzheimer's disease (AD) is a disorder characterised by a progressive deterioration in memory and other cognitive functions. Neurofibrillary tangles (NFT) are a major pathological hallmark of AD, these are aggregations of paired helical filaments (PHF) comprised of the hyperphosphorylated microtubule associated protein tau. Several kinases, such as glycogen synthase kinase 3 beta (GSK3beta) and c-Jun N-terminal kinase (JNK), phosphorylate tau at sites that are phosphorylated in PHF. Dishevelled 1 (DVL1) is thought to act as a positive regulator of the wnt signalling pathway, and inhibits GSK3beta activity preventing beta-catenin degradation and thus allowing wnt target gene expression. JNK activation is also regulated by DVL1, however it is unclear if this is via the wnt signalling pathway. These observations suggest a central role for DVL1 in tau phosphorylation and AD and led us to investigate DVL1 as a candidate gene for this disorder. We determined the genomic structure of the DVL1 gene by sequencing and data mining and searched for sequence variations in the coding sequences and flanking introns. The DVL1 gene spans a region of approximately 13.8 kb (not including the 5' untranslated region) and is encoded by 15 exons. Analysis of over 4.3 kb of sequence, including 98% of exonic sequences and introns 2, 3, 6, 7, 9, 10, 11 and 12, revealed there to be six rare (< or =6%) sequence variations. None of these had any association with late onset AD. This would suggest that polymorphic variations in the coding sequences of DVL1 are not important in AD. However further analysis of regulatory regions may lead to the identification of other sequence variations which may be implicated in AD.

Saito, Y., K. Suzuki, et al. (2002). "Niemann-Pick type C disease: Accelerated neurofibrillary tangle formation and amyloid beta deposition associated with apolipoprotein E varepsilon 4 homozygosity." Ann Neurol 52(3): 351-5.
Niemann-Pick type C disease is a neurovisceral storage disorder. Neurofibrillary tangles similar to those in Alzheimer's disease have been reported in most juvenile/adult patients without amyloid beta protein (Abeta) deposits. Recently, we found deposits of Abeta in the form of diffuse plaques in three (31- and 32-year-old sisters and a 37-year-old man) of nine Niemann-Pick type C disease patients, who presented with most severe tauopathy and with numerous neurofibrillary tangles. Abeta deposits were not detected in any of the control brains of patients younger than age 42 years. These three patients with Abeta deposit all were homozygotes of apolipoprotein E varepsilon 4. Our study suggested that NPC1 gene mutations combined with homozygosity of apolipoprotein E varepsilon 4 alleles could manifest neuropathology similar to that of Alzheimer's disease. Investigation of these patients may provide an important clue for understanding the pathogenesis of Alzheimer's disease.

Sato, S., Y. Tatebayashi, et al. (2002). "Aberrant tau phosphorylation by GSK-3b and JNK-3 induces oligomeric tau fibrils in COS-7 cells." J Biol Chem.
Neurofibrillary tangles (NFTs) are found in a wide range of neurodegenerative disorders, including Alzheimers disease (AD). The major component of NFTs is aberrantly hyperphosphorylated microtubule-associated protein tau. Because appropriate in vivo models have been lacking, the role of tau phosphorylation in NFTs formation has remained elusive. Here, we describe a new model in which adenovirus-mediated gene expression of tau, deltaMEKK, JNK3, and GSK-3b in COS-7 cells produces most of the pathological phosphorylation-epitopes of tau including AT100. Furthermore, this co-expression resulted in the formation of tau aggregates having short fibrils that were detergent insoluble and Thioflavin-S reactive. These results suggest that aberrant tau phosphorylation by the combination of these kinases may be involved in pretangle, oligomeric tau fibril formation in vivo.

Schneider, J. A., J. L. Bienias, et al. (2002). "Improved detection of substantia nigra pathology in Alzheimer's disease." J Histochem Cytochem 50(1): 99-106.
The role of substantia nigra pathology in Alzheimer's disease (AD) is uncertain. Detection of pathology may be obscured by intraneuronal neuromelanin and influenced by stains. We determined methods for optimal visualization of nigral pathology in 45 cases of AD. For detection of Lewy bodies (LBs), we compared ubiquitin and alpha-synuclein immunostains to hematoxylin and eosin (H&E). For neurofibrillary tangles (NFTs) and neuropil threads (NTs), we compared Gallyas silver and paired helical filament (PHF) immunostains, after bleaching of melanin, to modified Bielschowsky, Gallyas, and PHF alone. The number of LB cases was not different using the three stains. However, more LBs per section were detected using alpha-synuclein (z=4.88, p<0.001). Twice the number of cases exhibited NFT (z=8.21; p<0.001) and the mean NFT number per section was 2.8-5.2-fold greater, using Gallyas and PHF after bleaching compared to without bleaching (chi(2)=142.17; p<0.001). More NTs (z=6.54; p<0.001) were observed with PHF and Gallyas after bleaching. With optimal methods, we found LBs in 27%, NFTs in 89%, and NTs in all 45 AD cases. We show that detection of nigra pathology is influenced by histological method. Clinicopathological studies using these methods are needed to determine the role of nigral pathology in AD.

Schubert, C. (2002). "Flies tangle with tau." Nat Med 8(6): 565.

Scott, H. L., D. V. Pow, et al. (2002). "Aberrant expression of the glutamate transporter excitatory amino acid transporter 1 (EAAT1) in Alzheimer's disease." J Neurosci 22(3): RC206.
Glutamate-mediated toxicity has been implicated in the neurodegeneration observed in Alzheimer's disease. In particular, glutamate transport dysfunction may increase susceptibility to glutamate toxicity, thereby contributing to neuronal cell injury and death. In this study, we examined the cellular localization of the glial glutamate transporter excitatory amino acid transporter 1 (EAAT1) in the cerebral cortex of control, Alzheimer's disease, and non-Alzheimer dementia cases. We found that EAAT1 was strongly expressed in a subset of cortical pyramidal neurons in dementia cases showing Alzheimer-type pathology. In addition, tau (which is a marker of neurofibrillary pathology) colocalized to those same pyramidal cells that expressed EAAT1. These findings suggest that EAAT1 changes are related to tau expression (and hence neurofibrillary tangle formation) in dementia cases showing Alzheimer-type pathology. This study implicates aberrant glutamate transporter expression as a mechanism involved in neurodegeneration in Alzheimer's disease.

Selkoe, D. J. and M. B. Podlisny (2002). "Deciphering the genetic basis of Alzheimer's disease." Annu Rev Genomics Hum Genet 3: 67-99.
A remarkable rise in life expectancy during the past century has made Alzheimer's disease (AD) the most common form of progressive cognitive failure in humans. Compositional analyses of the classical brain lesions, the senile (amyloid) plaques and neurofibrillary tangles, preceded and has guided the search for genetic alterations. Four genes have been unequivocally implicated in inherited forms of AD, and mutations or polymorphisms in these genes cause excessive cerebral accumulation of the amyloid ss-protein and subsequent neuronal and glial pathology in brain regions important for memory and cognition. This understanding of the genotype-to-phenotype conversions of familial AD has led to the development of pharmacological strategies to lower amyloid ss-protein levels as a way of treating or preventing all forms of the disease.

Shoghi-Jadid, K., G. W. Small, et al. (2002). "Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease." Am J Geriatr Psychiatry 10(1): 24-35.
The authors used 2-(1-(6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononi trile ([18F]FDDNP), a hydrophobic radiofluorinated derivative of 2-(1-[6-(dimethylamino)-2-naphthyl]ethylidene)malononitrile (DDNP), in conjunction with positron emission tomography to determine the localization and load of neurofibrillary tangles (NFTs) and beta-amyloid senile plaques (APs) in the brains of living Alzheimer disease (AD) patients. Previous work illustrated the in vitro binding characteristics of [18F]FDDNP to synthetic beta-amyloid(1-40) fibrils and to NFTs and APs in human AD brain specimens. In the present study, greater accumulation and slower clearance was observed in AP- and NFT-dense brain areas and correlated with lower memory performance scores. The relative residence time of the probe in brain regions affected by AD was significantly greater in patients with AD (n=9) than in control subjects (n=7; p=0.0007). This noninvasive technique for monitoring AP and NFT development is expected to facilitate diagnostic assessment of patients with AD and assist in response-monitoring during experimental treatments.

Silver, M. H., K. Newell, et al. (2002). "Distinguishing between neurodegenerative disease and disease-free aging: correlating neuropsychological evaluations and neuropathological studies in centenarians." Psychosom Med 64(3): 493-501.
OBJECTIVE: In an examination of disease-free aging and neurodegenerative disease in 100-year-olds, the New England Centenarian Study compared data from neuropsychological evaluations with postmortem brain studies of fourteen 100-year-olds to ascertain if the presence or absence of Alzheimer disease changes correlated with measured cognitive abilities. METHODS: Fourteen of 74 centenarians who underwent annual extensive neuropsychological evaluation proceeded to postmortem neuropathological examination. CERAD criteria, emphasizing neuritic amyloid plaques and Braak and Braak staging of neurofibrillary tangles were used to assess the 14 brains. RESULTS: Neuropsychological and neuropathological findings correlated well for four subjects with no dementia on testing (CDR = 0) and for six subjects with CDR scores in the dementia range (CDR = 1-5). In the latter group, Alzheimer's disease was diagnosed in four brains; Pick's disease was an etiological factor in the fifth and hippocampal sclerosis in the sixth. Correlation was low for four subjects: two subjects with no dementia on neuropsychological testing met CERAD neuropathological criteria for possible AD; two subjects with dementia on testing did not meet CERAD criteria for definite Alzheimer's disease and had otherwise minimal changes to correlate with the cognitive findings. CONCLUSIONS: Lack of correlation between level of cognitive functioning and brain pathology in two subjects with no dementia raised the question of whether a functional reserve delayed the functional expression of pathological changes. For two subjects with dementia on testing, there appeared to be no sufficient pathological explanation for the extent of the cognitive changes; depression and such factors as environment, sensory impairment, and medical illness may all have played a role. There may also have been neuropathologic changes not detected by current methods.

Singer, S. M., G. M. Zainelli, et al. (2002). "Transglutaminase bonds in neurofibrillary tangles and paired helical filament tau early in Alzheimer's disease." Neurochem Int 40(1): 17-30.
Transglutaminase-catalyzed epsilon(gamma-glutamyl)lysine cross-links exist in Alzheimer's disease (AD) paired helical filament (PHF) tau protein but not normal soluble tau. To test the hypothesis that these cross-links could play a role in the formation of neurofibrillary tangles (NFT), we used single- and double-label immunofluorescence confocal microscopy and immunoaffinity purification and immunoblotting to examine epsilon(gamma-glutamyl)lysine cross-links in AD and control brains. The number of neurons that are immunoreactive with an antibody directed at the epsilon-(gamma-glutamyl)lysine bond was significantly higher in AD cortex compared with age-matched controls and schizophrenics. PHF tau-directed antibodies AT8, MC-1 and PHF-1 co-localized with epsilon(gamma-glutamyl)lysine immunolabeling in AD NFT. Immunoaffinity purification and immunoblotting experiments demonstrated that PHF tau contains epsilon(gamma-glutamyl)lysine bonds in parietal and frontal cortex in AD. In control cases with NFT present in the entorhinal cortex and hippocampus, indicative of Braak and Braak stage II, epsilon(gamma-glutamyl)lysine bonds were present in PHF tau in parietal and frontal cortex, despite the lack of microscopically detectable NFT or senile plaques in these cortical regions. The presence of PHF tau with epsilon(gamma-glutamyl)lysine bonds in brain regions devoid of NFT in stage II (but regions, which would be expected to contain NFT in stage III) suggests that these bonds occur early in the formation of NFT.

Small, G. W. (2002). "Brain-imaging surrogate markers for detection and prevention of age-related memory loss." J Mol Neurosci 19(1-2): 17-21.
Recent evidence points to the importance of neuropathological and cognitive changes preceding Alzheimer's disease (AD), and clinical trials have begun to focus on preventive treatments designed to slow age-related cognitive decline and delay the onset of AD in people with age-associated memory impairment (AAMI). Studying subjects with few deficits leads to diagnostic heterogeneity and a need for larger samples in order to detect active drug effects. In this report, I review results of recent studies designed to address such issues. Middle-aged and older adults with mild memory complaints were studied using brain imaging and measures of the major known genetic risk for AD, the apolipoprotein E-4 (APOE-4) allele. In a study of positron emission tomography during mental rest, glucose metabolic rates were significantly lower in APOE-4 carriers in brain regions affected by AD. Another study using functional magnetic resonance imaging showed increased brain activation during memory tasks in APOE-4 carriers in similar brain regions. Longitudinal follow-up after 2 yr indicated the potential utility of such brain-imaging measures, combined with genetic-risk information, as surrogate markers in treatment trials for AAMI to prevent further cognitive decline. Current development focuses on novel technologies using positron emission tomography to directly image the neuritic plaques and neurofibrillary tangles of AD in order to provide more specific measures of disease progression in future clinical trials.

Smith, M. A., K. L. Drew, et al. (2002). "Amyloid-beta, tau alterations and mitochondrial dysfunction in Alzheimer disease: the chickens or the eggs?" Neurochem Int 40(6): 527-31.
Alzheimer disease (AD) is defined pathologically and diagnostically defined by amyloid-beta senile plaques and neurofibrillary tangles (NFT) composed of tau. From the time of their original description nearly a century ago, a major focus has been to understand the role that these lesions play in the pathogenesis of the disease. The majority favors the notion that these lesions cause the disease and therefore attempts at therapeutic intervention are focused on preventing lesions formation. However, this rationale may be misguided since new evidence from our laboratories and others suggest that the lesions not only occur as a by-product of the fundamental disease process but also that they may be protective.

Sommer, B. (2002). "Alzheimer's disease and the amyloid cascade hypothesis: ten years on." Curr Opin Pharmacol 2(1): 87-92.
The amyloid beta peptide as the major culprit of Alzheimer's disease pathogenesis entered the research arena about a decade ago. The amyloid cascade hypothesis was vividly discussed, supported and contested. Has it held up to all challenges until today? It is alive as ever. The recent identification of the key enzyme involved in amyloid beta generation offered a new target for drug discovery and a novel therapy approach using immunization has successfully eliminated plaque burden in a transgenic mouse. Neurofibrillary tangles, the other hallmark of the disease, were induced in an animal model by amyloid beta peptide.

Sun, A., G. Koelsch, et al. (2002). "Localization of beta-secretase memapsin 2 in the brain of Alzheimer's patients and normal aged controls." Exp Neurol 175(1): 10-22.
Chronic accumulation of beta-amyloid in the brain has been shown to result in complex molecular and cellular changes that accompany neurodegeneration in Alzheimer's disease (AD). In this study, we examined the expression of a newly identified beta-secretase, memapsin 2 (M2) or beta-site APP cleaving enzyme in deparaffinized sections from 10 AD patients and 10 aged matched controls and in frozen samples of parietal cortex from 11 AD and 8 controls. M2 is mainly expressed in neurons, with high levels in CA4 to CA2 regions and transentorhinal cortex and low or intermediate levels in CA1, subiculum, and granule cells of the dentate gyrus. The majority of AD brains showed an increase of M2 expression in the CA1, but a decrease in the transentorhinal cortex. A subset of controls and AD patients had high M2 expression in parietal neocortex. Double-staining revealed that senile plaques are not directly associated with the soma of M2-expressing neurons. Neurofibrillary tangles were associated with lower M2 expression in AD. These data indicate that beta-secretase M2 may not be straightforwardly involved in amyloid plaque formation in AD brain.

Sun, A., X. V. Nguyen, et al. (2002). "Comparative analysis of an improved thioflavin-s stain, Gallyas silver stain, and immunohistochemistry for neurofibrillary tangle demonstration on the same sections." J Histochem Cytochem 50(4): 463-72.
An improved thioflavin-S stain, Gallyas silver stain, and two immunostainings were quantitatively compared for demonstration of neurofibrillary tangles (NFTs) on the same sections. Sections of hippocampal formation from seven cases of Alzheimer's disease (AD) were immunofluorescently stained with a commercially available polyclonal NFT antibody or a PHF-1 monoclonal antibody, followed by an improved thioflavin-S stain, and finally by Gallyas silver staining. The thioflavin-S method was improved by using a combination quenching method that removes background autofluorescence without remarkable tissue damage and by post-treatment with concentrated phosphate buffer, which minimizes photobleaching. PHF-1 or NFT immunostaining is much less sensitive than the improved thioflavin-S staining and Gallyas silver staining, particularly in the transentorhinal region. Moreover PHF-1 immunoreactivity varied greatly among AD individuals. Thioflavin-S staining and Gallyas silver staining show almost the same sensitivity in NFT demonstration, but only the former depends on the secondary protein structure of NFTs. This study suggests that the improved thioflavin-S staining is a simple, sensitive, and consistent method for demonstration of neurofibrillary pathology.

Szirmai, I. and T. Kovacs (2002). "[In Process Citation]." Ideggyogy Sz 55(7-8): 220-5.
The cognitive (executive) ability of patients with Parkinson's-disease (PD) deteriorates gradually during the progression of the disease. Fluency of speech, word finding, working memory, ability to plan the future and flexibility decline. Cognitive disturbance was found to be proportional with the speech, posture, gait and balance problems and can not be influenced by L-dopa substitution. Apart the dorsal and ventral mesolimbic dopaminergic systems the coerulo-cortical noradrenergic, serotoninergic and cholinergic systems are also impaired in PD. Subcortical dementia in PD can also be explained by the functional disability of dorsolateral and anterior cingular circuits. Attention deficit can be explained by the dopamine depletion of cingular cortex. Cortical Lewy bodies, neurofibrillary tangles, neurit plaques and additional vascular pathology should also play a role in cognitive impairment of PD. In several systemic degenerative diseases associating with Parkinson's syndrome (PS) i.e. progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA) dementia can be detected with various severity, therefore the question arises concerning the correlation between cognitive disability and PS. Parkinson syndrome can also develop in frontotemporal dementias (FTD), Alzheimer's disease and cortical Lewy body disease (CLBD) but no correlation exists between motor disability and severity of dementia. In CLBD dementia can be the initial symptom in 18% of cases but PS can also preceeds the dementia. In PSP profound depletion of other monoaminergic neurotransmitter system was also reported. In FTDs associated with PS degeneration of substantia nigra, locus coeruleus and basal nucleus of Meynert has been reported with increased number of neurofibrillary tangles. In patients with vascular PS (VP) there is generally no tremor and rigidity, but pseudobulbar palsy, dementia, gate disturbance, incontinency appears; L-dopa treatment is generally ineffective. In VP no cellular loss can be found within the substantia nigra, but leukoaraiosis, lacunae in the white matter and basal ganglia are commonly demonstrated.

Tabira, T., D. H. Chui, et al. (2002). "Significance of intracellular Abeta42 accumulation in Alzheimer's disease." Front Biosci 7: a44-9.
Abeta plays a pivotal role in the pathogenesis of Alzheimer's disease (AD), but it is still obscure how it causes AD. We have established transgenic mice carrying wild-type or familial Alzheimer's disease (FAD) mutant-type presenilin 1 (PS1). In these mice, the number of cortical and hippocampal neurons decreased along with age in mutant mice. In addition, the old mutant mice showed a significant increase of dark neurons by silver staining and the number of neurons with intracellular Abeta42 by immunohistochemistry. Our extended study also showed a significant increase of intracellular Abeta42-positive neurons in isolated cases of AD as well as in PS1 mutant FAD cases. These neurons frequently showed apoptotic staining. However, coincidence of apoptotic markers and intraneuronal neurofibrillary tangles (NFT) was insignificant. Notably intraneuronal Abeta42-labeling was frequently seen in a case of AD showing cotton-wool type senile plaques with a few NFT positive neurons and dystrophic neurites. These results indicate that intraneuronal deposition of Abeta42 is important in the pathogenesis of AD.

Takahashi, R. H., E. E. Nam, et al. (2002). "Alzheimer beta-amyloid peptides: normal and abnormal localization." Histol Histopathol 17(1): 239-46.
Alzheimer's disease (AD) neuropathology is characterized by accumulation of "senile" plaques (SPs) and neurofibrillary tangles (NFTs) in vulnerable brain regions. SPs are principally composed of aggregates of up to 42/43 amino acid beta-amyloid (A beta) peptides. The discovery of familial AD (FAD) mutations in the genes for the amyloid precursor protein (APP) and presenilins (PSs), all of which increase A beta42 production, support the view that A beta is centrally involved in the pathogenesis of AD. A beta42 aggregates readily, and is thought to seed the formation of fibrils, which then act as templates for plaque formation. A beta is generated by the sequential intracellular cleavage of APP by beta-secretase to generate the N-terminal end of A beta, and intramembranous cleavage by gamma-secretase to generate the C-terminal end. Cell biological studies have demonstrated that A beta is generated in the ER, Golgi, and endosomal/lysosomal system. A central question involving the role of A beta in AD concerns how A beta causes disease and whether it is extracellular A beta deposition and/or intracellular A beta accumulation that initiates the disease process. The most prevalent view is that SPs are composed of extracellular deposits of secreted A beta and that A beta causes toxicity to surrounding neurons as extracellular SP. The recent emphasis on the intracellular biology of APP and A beta has led some investigators to consider the possibility that intraneuronal A beta may directly cause toxicity. In this review we will outline current knowledge of the localization of both intracellular and extracellular A beta.

Takashima, A. (2002). "[Neurofibrillary tangles and neurodegenerative disease]." Seikagaku 74(6): 461-70.

Tanemura, K., M. Murayama, et al. (2002). "Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau." J Neurosci 22(1): 133-41.
Formation of neurofibrillary tangles (NFTs) is a common neuropathological feature found in several neurodegenerative diseases, including Alzheimer's disease. We have developed a transgenic (Tg) mouse expressing mutant human tau (V337M), derived from frontotemporal dementia parkinsonism-17. V337M Tg mice revealed tau aggregations in the hippocampus, which fulfills the histological criteria for NFTs in human neurodegenerative diseases. Concurrent with the accumulation of RNA and phosphorylated tau, neurons exhibited morphological characteristics of degenerating neurons, which include a loss of microtubules, accumulation of ribosomes, plasma and nuclear membrane ruffling, and swelling of the Golgi network. Thus, mutant tau induces neuronal degeneration associated with the accumulation of RNA and phosphorylated tau. The functional consequences of this neuronal degeneration was evidenced by the reduction of hippocampal neural activity and behavioral abnormality in Tg mice.

Tilleman, K., I. Stevens, et al. (2002). "Differential expression of brain proteins in glycogen synthase kinase-3 transgenic mice: a proteomics point of view." Proteomics 2(1): 94-104.
One of the landmarks of Alzheimer's disease are neurofibrillary tangles (NFT) in the brain. NFT mainly consist of a hyperphosphorylated form of the protein tau, which is responsible for stabilisation of the neuronal cytoskeleton by microtubule binding and is unable to function properly in its hyperphosphorylated form. Glycogen synthase kinase-3beta (GSK3beta) is able to phosphorylate tau in a cellular context which could play a role in the formation of these NFT. In order to learn more about the effect of GSK-3beta in the brain, two-dimensional electrophoresis patterns of cerebrum extracts of GSK3beta[S9A] transgenic mice and wild type mice were compared quantitatively. Fifty-one spots were identified as being different in integrated intensity by at least a factor 1.5. The spots were subsequently identified by mass spectrometry. Identification of several proteins linked to signal transduction pathways in which GSK3beta plays a role, indicates that our population of identified proteins includes some down stream proteins of GSK3beta. This study may contribute to filling the gaps between GSK3beta, its substrates and finally the phosphorylation of tau.

Togo, T. and D. W. Dickson (2002). "Tau accumulation in astrocytes in progressive supranuclear palsy is a degenerative rather than a reactive process." Acta Neuropathol (Berl) 104(4): 398-402.
Tau-immunoreactive astrocytes in progressive supranuclear palsy (PSP) have a distinctive morphology and are referred to as tufted astrocytes (TA). We hypothesized that TA may be a degenerative change in reactive astrocytes. To test this hypothesis we examined the relationship of TA to gliosis in PSP. We first examined the distribution of gliosis [glial fibrillary acid protein (GFAP)-positive astrocytes], TA, neurofibrillary tangles (NFT) and pretangles in brain sections of neuropathologically pure PSP cases. Second, we examined PSP cases complicated by infarcts or Alzheimer's disease, since these cases would have reactive astrocytes associated with lesions. We used double immunostaining for GFAP and tau for cases with vascular lesions, and triple immunostaining for GFAP, tau and beta-amyloid protein for sections with senile plaques. There was no correlation between the distribution of gliosis and TA, with gliosis prominent in globus pallidus and subthalamic nucleus, and TA prominent in motor cortex and striatum. On the other hand, gliosis paralleled the distribution of NFT, but not the distribution of pretangles, suggesting that NFT contributes to gliosis in PSP. Although reactive astrocytes were present around infarcts and senile plaques, TA were not associated with these lesions. Tau accumulation in astrocytes in PSP was not preferential to (and was actually independent of) reactive astrocytes. This is consistent with the notion that tau accumulation in astrocytes is a degenerative rather than reactive process. Unlike NFT, astrocytic degeneration does not seem to contribute to gliosis or neuronal loss in PSP, and its clinical significance remains unclear.

Torreilles, F. and J. Touchon (2002). "Pathogenic theories and intrathecal analysis of the sporadic form of Alzheimer's disease." Prog Neurobiol 66(3): 191-203.
Alzheimer's disease (AD) is an age-dependent dementia characterized by progressive loss of cognitive functions and by characteristic pathological changes in the brain: the formation of aggregates extracellularly by beta-amyloid (Abeta) peptide and intracellularly by tau proteins. The disease presents several major diagnostic difficulties: (1) AD develops slowly; (2) analysis of damaged brain tissues is difficult, requiring a biopsy which poses ethical problems; (3) no biochemical markers are available for the diagnosis and monitoring of the disease progression. Since the cerebrospinal fluid (CSF) is in contact with the extracellular space of the brain, many studies have tried to correlate the levels of the intrathecal peptides and amino acids and the development of dementia. The present review analyzes the main results of intrathecal content analyses in light of pathogenic theories proposed to explain the damage associated with AD and observed in the brain of patients by postmortem examination.

Town, T., J. Zolton, et al. (2002). "p35/Cdk5 pathway mediates soluble amyloid-beta peptide-induced tau phosphorylation in vitro." J Neurosci Res 69(3): 362-72.
Alzheimer's disease (AD) is pathologically characterized by deposition of amyloid-beta peptides (Abeta) as senile plaques and by the occurrence of neurofibrillary tangles (NFTs) composed primarily of hyperphosphorylated tau protein. Activation of cyclin-dependent kinase 5 (Cdk5) via its potent activator p25 has recently been shown to promote phosphorylation of tau at AD-specific phosphoepitopes, and increased cleavage of p35 to p25 has been demonstrated in AD patients, suggesting that Cdk5 may represent a pathogenic tau protein kinase. We were interested in the potential effect of soluble forms of Abeta on Cdk5-mediated AD-like tau phosphorylation, insofar as previous studies of human biopsies and aged canine and primate brains have shown that dystrophic neurites appear before the formation of neuritic plaques. We transfected N2a cells with a p35 vector (N2a/p35 cells) and, after differentiation, challenged these cells with Abeta(1-42) peptide in soluble form (sAbeta(1-42)). Results show that sAbeta(1-42) at relatively low levels (1-5 microM) dose-dependently increases tau phosphorylation at AD-specific phosphoepitopes in differentiated N2a/p35 cells compared with controls, an effect that is blocked by antisense oligonucleotides against p35. sAbeta(1-42)-induced tau phosphorylation is concomitant with an increase in both p25 to p35 ratio and Cdk5 activity (but not protein levels). Additionally, blockade of L-type calcium channels or inhibition of calpain completely abolishes this effect. Taken together, these data indicate that sAbeta is a potent activator of the p25/Cdk5 pathway, resulting in promotion of AD-like tau phosphorylation in vitro.

Tsuchiya, K., H. Nakayama, et al. (2002). "Distribution of basal ganglia lesions in diffuse neurofibrillary tangles with calcification: a clinicopathological study of five autopsy cases." Acta Neuropathol (Berl) 103(6): 555-64.
We investigated five Japanese autopsy cases of diffuse neurofibrillary tangles with calcification (DNTC), both clinically and pathologically, and examined the degree and distribution of the basal ganglia lesions, especially in the amygdala, striatum, pallidum, and substantia nigra. The lesions in the amygdala, striatum, and pallidum were classified into three categories (mild, moderate, and severe). The lesions in the substantia nigra were qualitatively judged, compared with normal controls. Severe dementia was observed in four cases neuropathologically showing pronounced neuronal loss in the cerebral cortex, but one case without neuronal loss in the cerebral cortex showed mild memory disturbance. Extrapyramidal signs were evident in three cases. Obvious neuronal loss in the substantia nigra with the presence of Lewy bodies was noticed in four cases. Basal ganglia lesions in all five cases were uniform: the amygdala showed severe to moderate lesions, the caudate nucleus moderate to slight lesions, and the putamen and pallidum slight lesions to normal. Furthermore, the lesions in the amygdala were more prominent in the basolateral group than in the corticomedial group, inconsistent with those in the amygdala of Alzheimer's disease. Moderate lesions were evident in the basolateral group of the amygdala in the case without neuronal loss in the cerebral cortex. In DNTC, the degree and distribution of the basal ganglia lesions, except for nigral lesions, were analogous to those found in Pick's disease with Pick bodies. These clinicopathological findings may contribute to the elucidation of the clinicopathological hallmarks in this disorder.

Vogelgesang, S., E. Schroeder, et al. (2002). "Activated microglia do not mediate the early deposition of Abeta in carriers of the apolipoprotein Eepsilon4 allele." Clin Neuropathol 21(3): 99-106.
Activated microglia are a prominent component of the senile plaques in end-stage Alzheimer's disease, but whether microglia contribute to the initiation of the lesions remains unknown. In a previous postmortem study of non-demented elderly cases, we found that amyloidogenesis is advanced by at least 10 years in carriers of the apoEepsilon4 allele. To determine whether microglia are involved in the initial stages of beta-amyloid pathogenesis and whether apoE genotype influences microglial activation, we quantified HLA-DR-immunoreactive microglia in the medial temporal lobe of 229 non-demented humans of various APOE genotypes who had died between 50 and 91 years of age. Our results show that the number of HLA-DR-immunoreactive microglia increases with advancing age in both the gray matter and the white matter. In contrast to amyloid plaques and neurofibrillary tangles, there is no significant correlation between apoE genotype and density of microglia, although apoEepsilon4 homozygotes tended to have more microglia than did other apoE groups. In sections double-immunostained for Abeta and activated microglia, activated microglia were associated with dense-cored plaques but not with diffuse plaques, suggesting that microglial activation is a relatively late event in the genesis of beta-amyloid. Activation of microglia thus appears not to be the initial impetus for Abeta-deposition in the elderly.

Wang, X., S. T. DeKosky, et al. (2002). "Genetic variation in alpha(1)-antichymotrypsin and its association with Alzheimer's disease." Hum Genet 110(4): 356-65.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by extracellular neuritic plaques and intracellular neurofibrillary tangles in brain parenchyma. Alpha-1-antichymotrypsin (ACT) is a component of plaque cores, can bind to Abeta, and has been proposed as a possible candidate gene for AD susceptibility. The genetic association between the ACT codon -17*A allele of the signal peptide polymorphism and AD has been shown in some, but not in all studies. One hypothesis is that the ACT codon -17*A allele is in linkage disequilibrium with unknown functional mutation(s) in the ACT gene. This study was undertaken to identify new mutation(s) in the ACT gene by PCR-SSCP-sequencing and, in conjunction with known mutations, to assess their role in affecting the risk of AD. A total of seven new point mutations were observed: 5'UTR(A-->G), Asp128Asn(G-->A), Ser250Ser(C-->T), Leu301Pro(T-->C), Thr324Thr(A-->G), G-->A in intron 4, and 3'UTR C-->A. Of these, mutations at codon 250, codon 324, intron 4 and 3'UTR showed a frequency of 1% or more. Of the known mutations, Thr-17Ala(A-->G), Lys76Lys(A-->G) and Leu241Leu(G-->A) occur at a polymorphic level. The ACT codon -17*A allele was associated with increased risk of AD (OR for AA vs TT: 1.71; 95% CI: 1.16-2.53; P=0.007), especially in the presence of the APOE*4 allele (OR for AA vs TT: 2.35; 95% CI: 1.13-4.85; P=0.02). The codon 241*A allele and the codon 250*T allele were associated with protective effects against AD (OR: 0.36; 95% CI: 0.13-0.86; P=0.02) (OR:0.39; 95% CI: 0.18-0.85; P=0.02). irrespective of the APOE*4 status. The codon 324*G allele was associated with a marginal protective effect (OR:0.57; 95% CI: 0.26-1.26; P=0.17). While the codon 241*A allele was in linkage disequilibrium with the codon -17*A allele, the codon 250*T and codon 324*G alleles were non-randomly associated with the codon -17*T allele. In contrast, the codon 76*G (OR:1.34; 95% CI: 0.92-1.95; P=0.13), codon 227*G (OR:3.96; 95% CI: 0.83-18.8; P=0.08) and intron 4*G (OR:1.47; 95% CI: 0.88-2.29; P=0.15) alleles were associated with a modest risk of AD, and all were in linkage disequilibrium with the codon -17*A allele. EH-based haplotype analysis showed that certain haplotypes are associated with either higher or lower risk of AD. Our data indicate that the ACT gene harbors several potentially important variable sites, which are associated with either an increased or decreased risk of AD. The non-random combination of risk and protective alleles may explain, in part, why the association studies regarding the ACT codon -17*A have been inconsistent, especially if the frequency of other ACT mutations varies between populations.

Wang, L., M. Zhu, et al. (2002). "[The application of Gallyas-Braak stainings in pathologic diagnosis of neurodegenerative diseases]." Zhonghua Nei Ke Za Zhi 41(2): 120-3.
OBJECTIVE: To evaluate the role of Gallyas silver staining in the diagnosis of neurodegenerative diseases. METHOD: Modified Gallyas-Braak staining method was used to investigate samples of the brain and spinal cord of 22 cases with neurodegenerative disease including Alzheimer's disease (AD), Parkinson's diseas (PD), Pick's disease, diffuse Lewy body disease (DLBD), progressive supranuclear palsy (PSP), diagnosed by clinical and routine pathologic method. 10 cases without clinical symptoms and pathologic abnormalities of the nervous system served as control. RESULT: As compared with Bodian staining, Gallyas-Braak staining demonstrated clearly neurofibrillary tangles in the hippocampus and the cortex of frontal and temperal lobe in all the cases with Alzheimer's disease, 6 cases with dementia of other causes and 3 normal aged. However, global neurofibrillary tangles in the midbrain and the basal ganglia were found only with Gallyas-Braak staining in 4 cases with both dementia and extrapyramidal features. In addition, tuft-shaped astrocytes were shown with this method in the motor cortex, basal ganglia, midbrain of the above 4 cases and astrocytic plaques in the same area in 2 cases of the 4 cases. In this connexion, pathologic findings in 2 of the 4 cases corresponded to PSP and those of the other two cases fufiled the diagnostic criteria of corticobasal degeneration (CBD) Oligodendroglial cytoplasmic inclusions in the white matter of the brain and the spinal cord were founded in 3 of the 4 cases with multiple system atrophy (MSA). This silver staining demonstrated as well a lot of argyrophilic grains in the neuropil of the temporal lobe and the hippocampus in one case with AD. CONCLUSION: Gallyas silver staining could better reveal not only Alzheimer-like neurofibrillary tangles but also different glial inclusions in other neurodegenerative diseases such as PSP, CBD and MSA. Consequently, it is of great value in the pathologic diagnosis and study of such degenerative diseases.

Wang, H. W., J. F. Pasternak, et al. (2002). "Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus." Brain Res 924(2): 133-40.
The dementia in Alzheimer disease (AD) is usually attributed to widespread neuronal loss in conjunction with the pathologic hallmarks of intracellular neurofibrillary tangles and extracellular plaques containing amyloid (A beta) in fibrillar form. Recently it has been demonstrated that non-fibrillar assemblies of A beta possess electrophysiologic activity, with the corollary that they may produce dementia by disrupting neuronal signaling prior to cell death. We therefore examined the effects of soluble oligomers of A beta(1-42) on long-term potentiation (LTP) and long-term depression (LTD), two cellular models of memory, in the dentate gyrus of rat hippocampal slices. Compared with vehicle controls, slices pre-incubated 60 min in the presence of A beta-derived diffusible ligands (ADDLs) showed no differences in threshold intensity to evoke a synaptic response, slope of field excitatory post-synaptic potentials (EPSPs), or the input/output function. Tetanus-induced LTP and reversal of LTD were strongly inhibited in ADDLs-treated slices whereas LTD was unaffected. These data suggest that soluble non-fibrillar amyloid may contribute to the pathogenesis of AD both by impairing LTP/memory formation at the cellular level and by creating 'neuroplasticity imbalance' manifested by unopposed LTD in the setting of impaired capacity for neural repair via reversal of LTD or LTP.

Yokota, O., S. Terada, et al. (2002). "NACP/alpha-synuclein immunoreactivity in diffuse neurofibrillary tangles with calcification (DNTC)." Acta Neuropathol (Berl) 104(4): 333-41.
Diffuse neurofibrillary tangles with calcification (DNTC) is a rare tangle-predominant dementia, as well as one of the tauopathies lacking Abeta deposition. It is characterized by temporo-frontal lobar atrophy, Fahr-type calcification and, histopathologically, numerous neurofibrillary tangles in the limbic system and neocortex. Recently, accumulation of alpha-synuclein (alphaS), the precursor of the non-beta amyloid component (NAC) of Alzheimer's disease, has been shown in diverse neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, multiple system atrophy and parkinsonism-dementia complex of Guam. To clarify whether alphaS accumulates in other neurodegenerative disorders, we investigated eight DNTC brains using immunohistochemistry and demonstrated remarkable alphaS deposition in the neurons and astrocytes in many anatomical regions. Abundant Lewy bodies were observed in the amygdala (seven cases) and hippocampus (seven cases), and, to a lesser degree, in the substantia nigra (six cases) and dorsal vagal nucleus (five cases). In the hippocampus, many Lewy neurites were distributed in the stratum oriens and stratum pyramidale in the CA2-3 and the subiculum. Furthermore, numerous NAC-positive astrocytes were detected in the hippocampus and temporal cortex. This investigation reveals that neurons and astrocytes are extensively involved in remarkable alphaS pathology in the DNTC brain, and that the alphaS pathology compounds the cardinal pathological features of tau pathology. These findings suggest that (1) DNTC shares a common pathophysiological background with Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy in which abnormal alphaS aggregation is observed, and (2) there is an interaction between alphaS and tau pathology that does not involve amyloid in DNTC.

Yokoyama, K., S. Ikebe, et al. (2002). "[A 68-year-old woman with dementia and parkinsonism]." No To Shinkei 54(2): 175-84.
We report a 68-year-old woman who developed progressive dementia and parkinsonism. She was well until 1990 when she was 58 years of age. She started to show memory loss. Four years later, she developed difficulty in dressing and behavioral problems such as eating rice with her hands, going out of her house without purposes, and difficulty in finding the rest room in her house. She was admitted to the neurology service of Hatsuishi Hospital on January 19, 1996, when she was 64 years of the age. On admission, she was alert but markedly demented. The score of Hansegawa Dementia Scale was 0/30. She was unable to make any coherent conversation. She appeared to have dressing apraxia but did not appear to have aphasia. Cranial nerves were intact. She walked in small steps with stooped posture. She did not have motor weakness but she showed plastic rigidity in all four limbs. No tremor or ataxia was noted. Deep tendon reflexes were within normal limits but the plantar response was extensor bilaterally. She continued to deteriorate after admission. In May of 1998, she started to fall. In June of 1998, she had a generalized convulsion. In January of 1999, she became unable to take foods orally and a gastrostomy was placed. She expired on May 29, 1990. She was discussed in a neurological CPC and the chief discussant arrived at the conclusion that the patient had Alzheimer's disease. The question was whether her parkinsonism was a part of her Alzheimer's disease or she had an additional disease to explain her parkinsonism. Post-mortem examination revealed moderate to marked atrophy of the frontal and the temporal lobes as well as in the limbic areas with dilatation of the lateral ventricles. Marked neuronal loss was noted in the CA 1 to the subiculum region with gliosis. Neurofibrillary tangles were seen in the remaining neurons. Neuropil threads were seen by Gallyas-Braak staining. Similar changes were seen in the parahippocampal gyrus and in the entorhinal cortex. Senile plaques were seen in the insular cortex and in other cortical areas. Cortical type Lewy bodies were seen in the cingulate cortex. The Meynert nucleus showed marked neuronal loss and gliosis. The substantia nigra and the locus coeruleus showed moderate loss of pigmented neurons. Lewy bodies were seen in these regions. The dorsal motor nucleus of the vagal nerve was retained, however, one Lewy body was observed. Pathologic diagnosis was Alzheimer's disease plus Parkinson's disease. It is an interesting question whether or not her parkinsonism was due to nigral lesion or frontal lesions. It is known that parkinsonism may complicate in advanced Alzheimer's disease not necessarily due to nigral lesion. On the other hand, in incidental Lewy body disease, the substantia nigra shows mild Parkinson's disease-like change without clinical parkinsonism. This patient appeared to have been a true complication of Alzheimer's disease and Parkinson's disease.

Zatloukal, K., C. Stumptner, et al. (2002). "p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases." Am J Pathol 160(1): 255-63.
Exposure of cells to stress, particularly oxidative stress, leads to misfolding of proteins and, if they are not refolded or degraded, to cytoplasmic protein aggregates. Protein aggregates are characteristic features of a variety of chronic toxic and degenerative diseases, such as Mallory bodies (MBs) in hepatocytes in alcoholic and non-alcoholic steatohepatitis, neurofibrillary tangles in neurons in Alzheimer's, and Lewy bodies in Parkinson's disease. Using 2D gel electrophoresis and mass spectrometry, we identified p62 as a novel MB component. p62 and cytokeratins (CKs) are major MB constituents; HSP 70, HSP 25, and ubiquitinated CKs are also present. These proteins characterize MBs as a prototype of disease-associated cytoplasmic inclusions generated by stress-induced protein misfolding. As revealed by transfection of tissue culture cells overexpressed p62 did not induce aggregation of regular CK filaments but selectively bound to misfolded and ubiquitinated CKs. The general role of p62 in the cellular response to misfolded proteins was substantiated by detection of p62 in other cytoplasmic inclusions, such as neurofibrillary tangles, Lewy bodies, Rosenthal fibers, intracytoplasmic hyaline bodies in hepatocellular carcinoma, and alpha1-antitrypsin aggregates. The presence of p62 along with other stress proteins and ubiquitin in cytoplasmic inclusions indicates deposition as aggregates as a third line of defense against misfolded proteins in addition to refolding and degradation.

Zekry, D., C. Duyckaerts, et al. (2002). "Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly." Acta Neuropathol (Berl) 103(5): 481-7.
The relative importance of vascular and Alzheimer's disease (AD) lesions, their interaction in the development of cognitive impairment and the very existence of mixed dementia induced by the potentiation of both mechanisms remain controversial. The aim of this study was to assess whether the patients with infarcts and lacunes have fewer plaques and tangles than those without vascular lesions, for similar severity of clinical dementia. We performed a prospective clinicopathological study in elderly patients of a long-stay care unit. The severity of clinical dementia was assessed by psychometry performed according to standardized methods less than 6 months before death. A volumetric study of cerebral vascular lesions was performed at post-mortem study of the brain. The density of neuritic plaques (SP), Amyloid beta focal deposits (A beta FD), and neurofibrillary tangles (NFT) in the temporal and frontal isocortex was quantified. According to DSM III criteria, 28 of the 33 patients for whom autopsies were performed had dementia. Twenty-four of the included patients had degenerative or vascular lesions, or both. The volume of infarcts and lacunes was significantly correlated with the severity of cognitive impairment. The density of SP, A beta FD and NFT in the temporal and frontal isocortex was significantly lower when vascular lesions were present. For similar clinical severity of dementia, there were fewer AD lesions in patients with vascular lesions than in those without vascular lesions.