Almkvist, O. and B. Winblad (1999). "Early diagnosis of Alzheimer dementia based on clinical and biological factors." Eur Arch Psychiatry Clin Neurosci 249 Suppl 3: 3-9.
Alzheimer's disease (AD) is common in elderly individuals; it causes distress for the patients and their relatives as well as large costs for the society. With the advent of symptomatic treatment at present and probable etiology-based cures in the future, it will be possible to relieve and put an end to these negative effects. Therefore, it is necessary to diagnose the disease as early as possible. In this review, we briefly summarize the state-of-the-art concerning various available clinical and biochemical methods for identifying AD. Increasing age, heritage, and presence of ApoE e4 allele have been confirmed as risk factors for AD as well as some putative factors (e.g., low education, hypertension, hypotension) based on epidemiological recent research. Selective impairment of episodic memory has been found to be a preclinical marker for future development of AD based on convergent data from asymptomatic AD-related mutation carriers, longitudinal studies of patients with mild cognitive impairment (MCI), and epidemiological studies of incident AD cases. Neurophysiological methods are inexpensive and useful for the identification of changes in brain dysfunction in AD and new promising methods are under development. Using magnetic resonance imaging (MRT), structural measurements of brain atrophy and specific brain structures such as the hippocampus have been reported to detect dementia development early in the course of disease. Similarly, functional measurements of brain activity (e.g., blood flow) have revealed that hypometabolism in bilateral parietotemporal brain areas early in the disease course. Finally, biochemical studies have demonstrated that certain proteins (e.g., tau the A beta 1-42/43 metabolite of the amyloid precursor protein) may be associated with the disease process in AD, although the specificity of these markers remains to be established. It is concluded that still no single marker of AD exists, which makes it necessary to rely on data from multiple sources in order to arrive at the best possible diagnosis of AD.

Alvarez, A., R. Toro, et al. (1999). "Inhibition of tau phosphorylating protein kinase cdk5 prevents beta-amyloid-induced neuronal death." FEBS Lett 459(3): 421-6.
The key target of this study was the tau protein kinase II system (TPK II) involving the catalytic subunit cdk5 and the regulatory component p35. TPK II is one of the tau phosphorylating systems in neuronal cells, thus regulating its functions in the cytoskeletal dynamics and the extension of neuronal processes. This research led to demonstration that the treatment of rat hippocampal cells in culture with fibrillary beta-amyloid (Abeta) results in a significant increase of the cdk5 enzymatic activity. Interestingly, the data also showed that the neurotoxic effect of 1-20 microM Abeta on primary cultures markedly diminished with co-incubation of hippocampal cells with the amyloid fibers plus the cdk5 inhibitor butyrolactone I. This inhibitor protected brain cells against Abeta-induced cell death in a concentration dependent fashion. Moreover, death was also prevented by a cdk5 antisense probe, but not by an oligonucleotide with a random sequence. The cdk5 antisense also reduced neuronal expression of cdk5 compared with the random oligonucleotide. The studies indicate that cdk5 plays a major role in the molecular path leading to the neurodegenerative process triggered by the amyloid fibers in primary cultures of rat hippocampal neurons. These findings are of interest in the context of the pathogenesis of Alzheimer's disease.

Alvarez, G., J. R. Munoz-Montano, et al. (1999). "Lithium protects cultured neurons against beta-amyloid-induced neurodegeneration." FEBS Lett 453(3): 260-4.
The deposition of beta-amyloid peptide (A beta), the hyperphosphorylation of tau protein and the death of neurons in certain brain regions are characteristic features of Alzheimer's disease. It has been proposed that the accumulation of aggregates of A beta is the trigger of neurodegeneration in this disease. In support of this view, several studies have demonstrated that the treatment of cultured neurons with A beta leads to the hyperphosphorylation of tau protein and neuronal cell death. Here we report that lithium prevents the enhanced phosphorylation of tau protein at the sites recognized by antibodies Tau-1 and PHF-1 which occurs when cultured rat cortical neurons are incubated with A beta. Interestingly, lithium also significantly protects cultured neurons from A beta-induced cell death. These results raise the possibility of using chronic lithium treatment for the therapy of Alzheimer's disease.

Andreasen, N., L. Minthon, et al. (1999). "Sensitivity, specificity, and stability of CSF-tau in AD in a community-based patient sample." Neurology 53(7): 1488-94.
OBJECTIVE: To evaluate the sensitivity and specificity of CSF-tau in clinical practice as a diagnostic marker for AD compared with normal aging and depression, to study the stability of CSF-tau in longitudinal samples, and to determine whether CSF-tau levels are influenced by different covariates such as gender, age, duration or severity of disease, or possession of the APOE-epsilon4 allele. METHODS: Consecutive AD patients from a community-based sample were studied, including 407 patients with AD (274 with probable AD and 133 with possible AD), 28 patients with depression, and 65 healthy elderly control subjects. A follow-up lumbar puncture was performed in 192 AD patients after approximately 1 year. CSF-tau was determined using a sandwich ELISA, which was run as a routine clinical neurochemical analysis. RESULTS: CSF-tau was increased in probable (690+/-341 pg/mL; p < 0.0001) and possible (661+/-447 pg/mL; p < 0.0001) AD, but not in depression (231+/-110 pg/mL) compared with control subjects (227+/-101 pg/mL). Receiver operating characteristics analysis showed that a cutoff level of 302 pg/mL resulted in a sensitivity of 93% (95% CI, 90-96%) and a specificity of 86% (95% CI, 75-94%), with an area under the curve of 0.95 to discriminate AD from control subjects. Within the AD group, CSF-tau did not differ significantly between baseline and follow-up investigations, and was relatively stable between baseline and 1-year follow-up levels, with a coefficient of variation of 21.0%. High CSF-tau levels were also found in most AD patients with very short duration of dementia, and with Mini-Mental State Examination scores >23 (n = 205). In total, 193 of 205 patients (sensitivity, 94%) had a CSF-tau level higher than 302 pg/mL. CONCLUSIONS: CSF-tau has a high sensitivity and specificity to differentiate AD from normal aging and depression, as demonstrated in a large community-based series of consecutive AD patients during which analyses were run continually in a clinical neurochemical laboratory. The increase in CSF-tau is found very early in the disease process in AD, is stable over time, and has a low interindividual variation on repeated sampling. Although high CSF-tau is found in some neurologic conditions (e.g., stroke), these findings suggest that CSF-tau may be of use to help in differentiating AD from normal aging and depression, especially early in the course of the disease, when the symptoms are vague and the diagnosis is especially difficult.

Andreasen, N., L. Minthon, et al. (1999). "Cerebrospinal fluid tau and Abeta42 as predictors of development of Alzheimer's disease in patients with mild cognitive impairment." Neurosci Lett 273(1): 5-8.
We studied CSF-tau and CSF-Abeta42 in 16 patients with mild cognitive impairment (MCI) who at follow-up investigations 6-27 months later had progressed to Alzheimer's disease (AD) with dementia. For comparison, we studied 15 age-matched healthy individuals. At baseline, 14/16 (88%) of MCI patients had high CSF-tau and/or low CSF-Abeta42 levels. These findings show that these CSF-markers are abnormal before the onset of clinical dementia and that they may help to identify MCI patients that will develop AD. This is especially important when drugs with potential effects on the progression of AD will reach the clinical phase.

Arai, K., E. Braak, et al. (1999). "Mossy fiber involvement in progressive supranuclear palsy." Acta Neuropathol (Berl) 98(4): 341-4.
The cerebellar cortex of progressive supranuclear palsy (PSP) cases exhibited a characteristic pathology which occurred neither in healthy aged individuals nor in cases of fully developed Alzheimer's disease. All of the 11 PSP cases studied reveal altered mossy fiber excrescences containing abnormal and hyperphosphorylated tau protein. Moreover, this abnormal material also appeared in cerebellar oligodendrocytes. Accordingly, there is not only the destruction of the cerebellar output system, which is already known, but also the involvement of the cerebellar input system.

Arendt, T., M. Holzer, et al. (1999). "Cortical load of PHF-tau in Alzheimer's disease is correlated to cholinergic dysfunction." J Neural Transm 106(5-6): 513-23.
To assess a potential relationship between cortical neurofibrillary degeneration and cortical cholinergic deafferentation, the load of PHF-tau was analysed in eight cortical regions and in the basal nucleus of Meynert in 12 cases with Alzheimer's disease by means of a sensitive ELISA employing the monoclonal antibody B5-2. The activity of choline acetyltransferase was determined on identical tissue samples. The results demonstrate a highly correlative relationship between the cortical distribution of the amount of PHF-tau, mainly present in neuropil threads, and cholinergic depletion early during the course of the disease. This relationship was less strong in more advanced stages. The results support the suggestion that the formation of PHF-tau in cholinergic axon terminals which might result in a loss of cholinergic synapses and a cholinergic dysconnection of the cortex, is an early event in AD. During the progression of the disease, formation of PHF-tau appears to spread over the cortex which results in a more even distribution of neuropil threads and a progressive involvement of non-cholinergic neurons.

Arima, K., S. Hirai, et al. (1999). "Cellular co-localization of phosphorylated tau- and NACP/alpha-synuclein-epitopes in lewy bodies in sporadic Parkinson's disease and in dementia with Lewy bodies." Brain Res 843(1-2): 53-61.
The precursor of the non-Abeta-component of Alzheimer's disease (AD) amyloid (NACP, alpha-synuclein) aggregates into insoluble filaments of Lewy bodies (LBs) in Parkinson's disease (PD) and dementia with LBs (DLB). The microtubule-associated protein tau is an integral component of filaments of neurofibrillary tangles (NFTs). NFTs are occasionally found in brains of PD and DLB; however, the presence of NFTs or tau-epitopes within LB-containing neurons is rare. Double-immunofluorescence study and peroxidase-immunohistochemical study in serial sections, performed to examine the co-localization of tau- and NACP-epitopes in the brainstem of PD and DLB, demonstrated that four different epitopes of tau including phosphorylation-dependent and independent ones were present in a minority of LBs, but more often than previously considered. A tau (tau2)-epitope was localized to filaments in the outer layers of brainstem-type LBs by immunoelectron microscopy. Therefore, we conclude that tau is incorporated into filaments in certain LBs. Extensive investigation has enabled us to classify this co-localization into four types: type 1, LBs with ring-shaped tau-immunoreactivity; type 2, LBs surrounded by NFTs; type 3, NACP- and tau-immunoreactive filamentous and granular masses; and type 4, NACP- and tau-immunoreactive dystrophic neurites. This study raises a new question whether aggregation and hyperphosphorylation of tau in PD and DLB are triggered by the collapse of intraneuronal organization of microtubules due to NACP-filament aggregation in neuronal perikarya and axons.

Armstrong, R. A., N. J. Cairns, et al. (1999). "Clustering of cerebral cortical lesions in patients with corticobasal degeneration." Neurosci Lett 268(1): 5-8.
Clustering of ballooned neurons (BN) and tau positive neurons with inclusion bodies (tau+ neurons) was studied in the upper and lower laminae of the frontal, parietal and temporal cortex in 12 patients with corticobasal degeneration (CBD). In a significant proportion of brain areas examined, BN and tau+ neurons exhibited clustering with a regular distribution of clusters parallel to the pia mater. A regular pattern of clustering of BN and tau+ neurons was observed equally frequently in all cortical areas examined and in the upper and lower laminae. No significant correlations were observed between the cluster sizes of BN or tau+ neurons in the upper compared with the lower cortex or between the cluster sizes of BN and tau+ neurons. The results suggest that BN and tau+ neurons in CBD exhibit the same type of spatial pattern as lesions in Alzheimer's disease, Lewy body dementia and Pick's disease. The regular periodicity of the cerebral cortical lesions is consistent with the degeneration of the cortico-cortical projections in CBD.

Behl, C. (1999). "Alzheimer's disease and oxidative stress: implications for novel therapeutic approaches." Prog Neurobiol 57(3): 301-23.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a deadly outcome. AD is the leading cause of senile dementia and although the pathogenesis of this disorder is not known, various hypotheses have been developed based on experimental data accumulated since the initial description of this disease by Alois Alzheimer about 90 years ago. Most approaches to explain the pathogenesis of AD focus on its two histopathological hallmarks, the amyloid beta protein- (A(beta)-) loaded senile plaques and the neurofibrillary tangles, which consist of the filament protein tau. Various lines of genetic evidence support a central role of A(beta) in the pathogenesis of AD and an increasing number of studies show that oxidation reactions occur in AD and that A(beta) may be one molecular link between oxidative stress and AD-associated neuronal cell death. A(beta) itself can be neurotoxic and can induce oxidative stress in cultivated neurons. A(beta) is, therefore, one player in the concert of oxidative reactions that challenge neurons besides inflammatory reactions which are also associated with the AD pathology. Consequently, antioxidant approaches for the prevention and therapy of AD are of central interest. Experimental as well as clinical data show that lipophilic antioxidants, such as vitamin E and estrogens, are neuroprotective and may help patients suffering from AD. While an additional intensive elucidation of the cellular and molecular events of neuronal cell death in AD will, ultimately, lead to novel drug targets, various antioxidants are already available for a further exploitation of their preventive and therapeutic potential. reserved

Bi, X., J. Zhou, et al. (1999). "Lysosomal protease inhibitors induce meganeurites and tangle-like structures in entorhinohippocampal regions vulnerable to Alzheimer's disease." Exp Neurol 158(2): 312-27.
Lysosomal protease inhibitors induce signs of human brain aging in rat hippocampal slices. The present studies tested if they (1) also cause neurofibrillary tangles and (2) reproduce regional patterns of pathology found in Alzheimer's disease (AD). Slices of hippocampus plus retrohippocampal cortex were prepared from rats at postnatal days 6-7 and maintained for 2-5 weeks. In agreement with earlier studies, 6- to 12-day infusions of selective (ZPAD) or generalized (chloroquine) inhibitors of lysosomal proteases generated meganeurites of the type found in aged human cortex. Surveys and quantitative analyses established that the meganeurites developed almost exclusively in AD vulnerable regions. Antibodies against the phosphorylated tau protein in neurofibrillary tangles labeled thick filaments running through neurons in the superficial layers of entorhinal cortex in 6-day ZPAD-treated slices. The general appearance of the stained structures resembled that of early stage tangles. More mature tangle-like profiles were found at a number of sites after longer incubations; these were threefold more frequent in the superficial (AD vulnerable) than in the deep layers of the entorhinal cortex. Immunoblots indicated that essentially all phosphorylated tau labeling in the slices involved approximately 29-kDa fragments of the native isoforms. These findings establish that lysosomal dysfunction triggers the parallel formation of meganeurites and tangles with the regional distribution of both effects reflecting that for AD vulnerability.

Biernat, J. and E. M. Mandelkow (1999). "The development of cell processes induced by tau protein requires phosphorylation of serine 262 and 356 in the repeat domain and is inhibited by phosphorylation in the proline-rich domains." Mol Biol Cell 10(3): 727-40.
The differentiation of neurons and the outgrowth of neurites depends on microtubule-associated proteins such as tau protein. To study this process, we have used the model of Sf9 cells, which allows efficient transfection with microtubule-associated proteins (via baculovirus vectors) and observation of the resulting neurite-like extensions. We compared the phosphorylation of tau23 (the embryonic form of human tau) with mutants in which critical phosphorylation sites were deleted by mutating Ser or Thr residues into Ala. One can broadly distinguish two types of sites, the KXGS motifs in the repeats (which regulate the affinity of tau to microtubules) and the SP or TP motifs in the domains flanking the repeats (which contain epitopes for antibodies diagnostic of Alzheimer's disease). Here we report that both types of sites can be phosphorylated by endogenous kinases of Sf9 cells, and that the phosphorylation pattern of the transfected tau is very similar to that of neurons, showing that Sf9 cells can be regarded as an approximate model for the neuronal balance between kinases and phosphatases. We show that mutations in the repeat domain and in the flanking domains have opposite effects. Mutations of KXGS motifs in the repeats (Ser262, 324, and 356) strongly inhibit the outgrowth of cell extensions induced by tau, even though this type of phosphorylation accounts for only a minor fraction of the total phosphate. This argues that the temporary detachment of tau from microtubules (by phosphorylation at KXGS motifs) is a necessary condition for establishing cell polarity at a critical point in space or time. Conversely, the phosphorylation at SP or TP motifs represents the majority of phosphate (>80%); mutations in these motifs cause an increase in cell extensions, indicating that this type of phosphorylation retards the differentiation of the cells.

Bigio, E. H., D. F. Brown, et al. (1999). "Progressive supranuclear palsy with dementia: cortical pathology." J Neuropathol Exp Neurol 58(4): 359-64.
Patients with progressive supranuclear palsy (PSP) often develop dementia, and cortical pathology has been documented in PSP. However, there are no reports correlating dementia in PSP with cortical pathology. We hypothesized that cases of PSP presenting with cognitive impairment would have more severe cortical tau pathology than those without. We compared 7 cases of PSP presenting with cognitive deficits (group 1) with 4 cases of PSP that did not (group 2). The subcortical tau pathology was almost identical in both groups. The cortical tau pathology was strikingly different in group 1, in which it was on average moderate, compared with group 2, in which it was minimal. The accumulation of cortical neuronoglial tau in PSP cases with dementia suggests that neurofibrillary pathology is central to the cause of dementia in PSP.

Bonkale, W. L., R. F. Cowburn, et al. (1999). "A quantitative autoradiographic study of [3H]cAMP binding to cytosolic and particulate protein kinase A in post-mortem brain staged for Alzheimer's disease neurofibrillary changes and amyloid deposits." Brain Res 818(2): 383-96.
The cAMP-dependent protein kinase (PKA) has been implicated in the Alzheimer's disease pathology of abnormal tau phosphorylation leading to neurofibrillary tangle (NFT) formation, as well as in amyloid precursor protein alpha-secretase processing. In the present study, we determined whether [3H]cAMP binding to cytosolic and particulate PKA showed any relationship to the extent of Alzheimer's disease pathology at post-mortem. Autoradiographic [3H]cAMP binding to cytosolic and particulate PKA was measured in sections of entorhinal cortex/hippocampal formation from 23 cases that had been staged for Alzheimer's disease-related neurofibrillary changes and amyloid deposits according to Braak and Braak [H. Braak, E. Braak, Neuropathological staging of Alzheimer's-related changes, Acta Neuropathol. 82 (1991) 239-259]. [3H]cAMP binding to cytosolic PKA showed statistically significant reductions in the entorhinal cortex (P<0.01, ANOVA) with respect to neurofibrillary changes. Post-hoc analysis with Fisher's PLSD test showed significant reductions of [3H]cAMP binding to cytosolic PKA at the isocortical stages (V and VI), compared to the non-pathological (O) (by 55%, P<0.01), transentorhinal (I and II) (by 58%, P<0.001) and limbic (III and IV) (by 45%, P<0.05) stages. A significant reduction (by 25%, P<0.05) was also seen in the transentorhinal compared to the limbic stages. [3H]cAMP binding to cytosolic PKA showed no significant alterations with respect to neurofibrillary changes in either the subiculum, CA1-CA4 subfields of the hippocampus or the dentate gyrus. [3H]cAMP binding to cytosolic PKA also showed significant declines in the entorhinal cortex (P<0.01) and subiculum (P<0.05) with respect to staging for amyloid deposits. Post-hoc analysis with Fisher's PLSD test showed significant reductions of [3H]cAMP binding to cytosolic PKA in the entorhinal cortex at amyloid stage C compared to stages O (by 41%, P<0.01) and A (by 38%, P<0.01). In the subiculum, there were significant reductions of [3H]cAMP binding at stages C (by 41%, P<0.01) and B (by 40%, P<0.05), respectively, compared to stage O. [3H]cAMP binding to particulate PKA did not show significant relationships to staging for either neurofibrillary changes or amyloid deposits in either the entorhinal cortex or any of the hippocampal subregions. These findings suggest that whereas [3H]cAMP binding to cytosolic PKA in the entorhinal cortex is reduced with progression of neurofibrillary and amyloid pathology, other hippocampal regions show a preservation of cytosolic and particulate PKA even in late stage pathologies.

Botez, G., A. Probst, et al. (1999). "Astrocytes expressing hyperphosphorylated tau protein without glial fibrillary tangles in argyrophilic grain disease." Acta Neuropathol (Berl) 98(3): 251-6.
Argyrophilic grain disease (AgD), a frequent type of late onset dementia, is characterized by the occurrence of Gallyas-stained neuropil grains in the hippocampus, entorhinal cortex, amygdala and hypothalamus. High numbers of neurons containing hyperphosphorylated tau protein, but devoid of tangles, are encountered in areas rich in argyrophilic grains (ArGs). A third type of change consists of slender argyrophilic and tau-immunoreactive cytoplasmic inclusions in white matter oligodendrocytes, the coiled bodies. We now extend earlier studies on glial pathology in AgD (20 cases) and compare the results with glial changes in old age (10 cases) and Alzheimer's disease (AD; 7 cases). Numerous non-argyrophilic, non-neuronal tau-positive stellate cells in the amygdala and anterior entorhinal cortex were consistently found in all of the 20 AgD cases but not in AD cases. Double-labelling experiments performed on paraffin sections with phosphorylation-dependent anti-tau antibody AT8, anti-glial fibrillary acidic protein and anti-CD44, revealed coexpression of these markers in stellate cells. The high expression of CD44 indicate that they probably correspond to reactive astrocytes. Unlike astrocytic plaques in corticobasal degeneration (CBD), where AT8 reactivity is accumulating in distal astrocytic processes, tau reactivity in AgD was found in all astrocytic cell compartments. The absence of glial fibrillary tangles further distinguished tau-labelled astrocytes in AgD from astrocytic plaques in CBD and tufted astrocytes in progressive supranuclear palsy (PSP). In contrast to AD and aged non-demented control cases tau-positive non-argyrophilic astrocytes represent a consistent finding in anterior limbic structures in AgD. Our findings point to a more widespread pathology of the glial cell population in AgD than previously supposed, and will be of further help in differentiating AgD from other neurodegenerative disorders, including AD, PSP, CBD and Pick's disease.

Braak, E., K. Griffing, et al. (1999). "Neuropathology of Alzheimer's disease: what is new since A. Alzheimer?" Eur Arch Psychiatry Clin Neurosci 249 Suppl 3: 14-22.
Alzheimer's disease results from severe cytoskeletal alterations in only a few neuronal types within the human central nervous system. These intraneuronal changes take the form of neurofibrillary tangles and neuropil threads. Beginning in predisposed induction sites in the allocortex, the lesions follow a predictable sequence as they engulf other territories of the cerebral cortex and a specific set of subcortical nuclei. Some components of the brain are devastated, while others remain intact until the end phase of the disease. Assessment of the location of the afflicted neurons and the severity of the lesions allows the distinction of stages in the development of the disease. The degenerative process begins with the emergence of the first lesions, at whatever age it occurs. The illness remains subclinical for years, and proceeds inexorably, gradually laying waste to higher order limbic system centers. Clinical symptoms are observed only late in the course of the disease, and their appearance is usually concurrent with the encroachment of the destructive process upon neocortical association areas. The sequence of destruction bears a striking resemblance to the inverse sequence of cortical myelination. Late myelinating areas and layers develop the disease-related changes earlier and at higher densities than those which are myelinated early. The brain of the human adult is heavily laden with intraneuronal deposits of lipofuscin and neuromelanin pigment. The average density of neuronal pigmentation in given cortical areas mirrors the density of cytoskeletal lesions that develop in the course of the disease. Pigment-laden neuronal types giving rise to a single long, thin, unmyelinated or sparsely myelinated axon are particularly prone to developing Alzheimer's disease-related cytoskeletal changes.

Brion, J. P. (1999). "[Neurofibrillary tangles and early modification of the neuronal cytoskeleton in Alzheimer's disease and in experimental models]." Bull Mem Acad R Med Belg 154(6 Pt 2): 287-94.
Neurofibrillary tangles, a hallmark neuropathological lesion of Alzheimer's disease and of the other tauopathies, are composed of hyperphosphorylated tau proteins (a microtubule-associated protein) assembled in the form of abnormal filaments. Hyperphosphorylation of tau proteins appears to be an early phenomenom, preceding their aggregation into fibrillar structures. This hyperphosphorylation could result from changes in the activation of signalling cascades. Presenilins, and their mutations, could be responsible for these changes and, by their ability to interfere with APP metabolism, play a central role in the formation of both neurofibrillary tangles and A beta amyloid deposits.

Brion, J. P., G. Tremp, et al. (1999). "Transgenic expression of the shortest human tau affects its compartmentalization and its phosphorylation as in the pretangle stage of Alzheimer's disease." Am J Pathol 154(1): 255-70.
We have generated transgenic mice expressing the shortest human tau protein, the microtubule-associated protein that composes paired helical filaments in Alzheimer's disease. Transgenic tau transcripts and proteins were strongly expressed in neurons in the developing and adult brain. In contrast to the endogenous tau that progressively disappeared from neuronal cell bodies during development, the human transgenic tau remained abundant in cell bodies and dendrites of a subset of neurons in the adult. This somatodendritic transgenic tau was immunoreactive with antibodies to tau phosphorylated on Thr181 and Thr231 and with the conformation-dependent Alz50 antibody. A few astrocytes expressing the transgenic tau were strongly immunoreactive with antibodies to additional tau phosphorylation sites, ie, at Ser262/ 356 and Ser396/404. All of these phosphorylation sites have been identified in paired helical filaments-tau proteins. In electron microscopy, the transgenic tau was detected into microtubules in axons and in dendrites but not in cell bodies. Neurofibrillary tangles were not detected in transgenic animals examined up to the age of 19 months. These results indicate that transgenic manipulation of tau expression and intracellular targeting is sufficient per se to affect tau compartmentalization, phosphorylation, and conformation partly as it is observed at the pretangle stage in Alzheimer's disease.

Bruckner, G., D. Hausen, et al. (1999). "Cortical areas abundant in extracellular matrix chondroitin sulphate proteoglycans are less affected by cytoskeletal changes in Alzheimer's disease." Neuroscience 92(3): 791-805.
In the human brain, the distribution of perineuronal nets occurring as lattice-like neuronal coatings of extracellular matrix proteoglycans ensheathing several types of non-pyramidal neurons and subpopulations of pyramidal cells in the cerebral cortex is largely unknown. Since proteoglycans are presumably involved in the pathogenesis of Alzheimer's disease, we analysed the distribution pattern of extracellular chondroitin sulphate proteoglycans in cortical areas, including primary motor, primary auditory and several prefrontal and temporal association areas, in normal human brains and in those showing neuropathological criteria of Alzheimer's disease. In both groups, neurons with perineuronal nets were most numerous in the primary motor cortex (approximately 10% in Brodmann's area 4) and in the primary auditory cortex as a representative of the primary sensory areas. Their number was lower in secondary and higher order association areas. Net-associated pyramidal cells occurred predominantly in layers III and V in motor areas, as well as throughout lower parts of layer III in the primary auditory cortex and neocortical association areas. In the entorhinal cortex, net-associated pyramidal cells were extremely rare. In brains showing hallmarks of Alzheimer's disease, the characteristic patterns of hyperphosphorylated tau protein, stained with the AT8 antibody, largely excluded the zones abundant in perineuronal nets and neuropil-associated chondroitin sulphate proteoglycans. As shown in double-stained sections, pyramidal and non-pyramidal neurons ensheathed by perineuronal nets were virtually unaffected by the formation of neurofibrillary tangles even in severely damaged regions. The distribution patterns of amyloid B deposits overlapped but showed no congruence with that of the extracellular chondroitin sulphate proteoglycans. It can be concluded that low susceptibility of neurons and cortical areas to neurofibrillary changes corresponds with high proportions of aggregating chondroitin sulphate proteoglycans in the neuronal microenvironment.

Buee, L. and A. Delacourte (1999). "Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick's disease." Brain Pathol 9(4): 681-93.
Neurodegenerative disorders referred to as tauopathies have cellular hyperphosphorylated tau protein aggregates in the absence of amyloid deposits. Comparative biochemistry of tau aggregates shows that they differ in both phosphorylation and content of tau isoforms. The six tau isoforms found in human brain contain either three (3R) or four microtubule-binding domains (4R). In Alzheimer's disease, all six tau isoforms are abnormally phosphorylated and aggregate into paired helical filaments. They are detected by immunoblotting as a major tau triplet (tau55, 64 and 69). In corticobasal degeneration and progressive supranuclear palsy, only 4R-tau isoforms aggregate into twisted and straight filaments respectively. They appear as a major tau doublet (tau64 and 69). Finally, in Pick's disease, only 3R-tau isoforms aggregate into random coiled filaments. They are characterized by another major tau doublet (tau55 and 64). These differences in tau isoforms may be related to either the degeneration of particular cell populations in a given disorder or aberrant cell trafficking of particular tau isoforms. Finally, recent findings provide a direct link between a genetic defect in tau and its abnormal aggregation into filaments in fronto-temporal dementia with Parkinsonism linked to chromosome 17, demonstrating that tau aggregation is sufficient for nerve cell degeneration. Thus, tau mutations and polymorphisms may also be instrumental in many neurodegenerative disorders.

Bugiani, O. (1999). "Pathogenesis of Alzheimer's disease and dementia." Rev Neurol (Paris) 155 Suppl 4: S28-32.
The pathogenesis of Alzheimer's disease is far from clear since it is still undetermined whether and how extracellular beta-protein and cytoskeletal degeneration of neurons, which are colocalized in the association neocortex of Alzheimer patients, are related to one another. By using beta-protein and other derivatives of the precursor protein, efforts to cause cell lesions comparable to neurofibrillary degeneration have been fruitless. However, the view that the amyloid issued from the polymerisation of beta-protein is neurotoxic, remains the most attractive. To fully explore this hypothesis, attention should be paid to neurons that participate in neocortical circuits and to factors that may influence their vulnerability, whether selective or not, to beta-protein and associated proteins.

Burger nee Buch, K., F. Padberg, et al. (1999). "Cerebrospinal fluid tau protein shows a better discrimination in young old (<70 years) than in old old patients with Alzheimer's disease compared with controls." Neurosci Lett 277(1): 21-4.
Tau protein is consistently reported to be elevated in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). CSF tau alone, however, is not a clinically useful diagnostic marker due to its relatively low diagnostic specificity. Therefore, efforts are under way to combine tau measurements with other criteria in order to improve diagnostic applicability. We investigated whether age could serve as an useful criterion to increase diagnostic accuracy. CSF levels of tau were measured in young old (<70 years) and old old (> or =70 years) patients with probable AD, elderly patients with major depression (MD), and age-matched healthy controls (HC). In AD patients, CSF tau levels were significantly elevated compared with MD patients and HC (P < 0.001). Based on a previously established cut-off of 260 pg/ml, the discriminative power was higher in the young old than in the old old subjects. Similarly, receiver operating characteristics analysis revealed a statistically significant higher correct classification rate in the young old. Our findings indicate that the discriminative power of CSF tau is higher in the young than in the old old. We suggest that the effect of age should be considered in studies investigating CSF tau as a diagnostic marker for neurodegenerative disorders.

Bussiere, T., P. R. Hof, et al. (1999). "Phosphorylated serine422 on tau proteins is a pathological epitope found in several diseases with neurofibrillary degeneration." Acta Neuropathol (Berl) 97(3): 221-30.
Neuronal inclusions with bundles of abnormal filaments made of tau polymers are found in numerous diseases with neurofibrillary degeneration. Tau proteins are the basic components of paired helical filaments (PHF) in Alzheimer's disease (AD), and are abnormally phosphorylated. A disease-specific phosphorylation site at serine422 was demonstrated on PHF, but not on tau proteins from biopsy-derived brain samples. In the present study, we report the characterization of a polyclonal antibody (988) against the serine422 phosphorylation site. By using biochemical and immunohistochemical methods, we confirmed that it is not found on tau proteins from biopsy- or autopsy-derived control samples, and we investigated the presence of this epitope on tau proteins in several neurodegenerative disorders, including AD, Down syndrome (DS), Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), postencephalitic parkinsonism (PEP) and Pick's disease (PiD). By Western blotting, antibody 988 labeled the characteristic tau triplet (tau 55, 64, 69) in AD, DS, Guamanian ALS/PDC and PEP. PSP and CBD exhibited their typical tau doublet (tau 64, 69), whereas the doublet tau 55 and 64 was detected in PiD. In all of these neurodegenerative disorders, antibody 988 clearly labeled NFT and dystrophic neurites, as well as Pick bodies in PiD cases, whereas no staining was observed in control cases. These data indicate that phosphorylation of serine422 on tau proteins is a common feature among neurodegenerative disorders and is therefore not specific of AD. Moreover, phosphorylation of this epitope permits the distinction between normal tau proteins and pathological tau proteins.

Chambers, C. B., J. M. Lee, et al. (1999). "Overexpression of four-repeat tau mRNA isoforms in progressive supranuclear palsy but not in Alzheimer's disease." Ann Neurol 46(3): 325-32.
Perturbations in the microtubule-associated protein tau occur in several human neurodegenerative diseases. In Alzheimer's disease and progressive supranuclear palsy (PSP), tau proteins assemble into straight and paired helical filaments that form intraneuronal deposits of neurofibrillary tangles (NFTs). The mechanisms underlying the aberrant assembly of tau into NFTs is unknown. To determine whether alterations in the expression of the carboxyl-terminal variants of tau contribute to NFT formation, we analyzed tau mRNA isoform expression in select regions of control, Alzheimer's disease, and PSP brains. In Alzheimer's disease, there were no alterations in tau mRNA isoform expression. However, in PSP, the levels of tau mRNA isoforms containing four microtubule binding domains were increased in the brainstem but not the frontal cortex or cerebellum. The brainstem in PSP has extensive NFT pathology, whereas the frontal cortex and cerebellum are relatively spared, suggesting that alterations in tau mRNA isoform expression occur in NFT-vulnerable regions in this disease. An increase in the four-repeat tau mRNA may lead to an increase in four-repeat tau protein isoforms and may contribute to the formation of NFTs in PSP. A similar increase in four-repeat tau mRNA has been reported for mutations associated with frontotemporal dementia and parkinsonism linked to chromosome 17.

Chen, L., L. Baum, et al. (1999). "Apolipoprotein E genotype and its pathological correlation in Chinese Alzheimer's disease with late onset." Hum Pathol 30(10): 1172-7.
In this study, we attempted to find a relationship between apoliprotein E (ApoE) genotypes and Alzheimer's disease (AD) pathology in different areas of the brain in Chinese. We also studied the borderline group of possible AD (Poss). There were 34 definite or probable AD (Ad), 18 Poss, and 123 brains from age-matched normal subjects (N). ApoE genotype was determined by nested polymerase chain reaction on genomic DNA extracted from archival paraffin-embedded materials. Hippocampus (including entorhinal cortex), amygdala, superior temporal lobe, middle frontal gyrus, and inferior parietal lobule of the brains of Ad and Poss were examined with beta amyloid (A beta) immunostaining, and the same regions plus medial occipital lobe were examined with tau immunostaining. The percentage of plaque area stained for A beta in each brain region was obtained by an image analyzer, and the average number of neurofibrillary tangles stained for tau was counted with an eyepiece graticule. ApoE epsilon4 frequency was increased in both Ad (22.1%, chi2, df = 1, P = .00005), and Poss (33.3%, P = .000005) compared with N (5.3%). A beta load was significantly increased in the neocortex in Ad examined with at least 1 copy of epsilon4 compared with subjects without epsilon4 (Mann-Whitney, P = .014). The same trend, though not statistically significant, occurred in Poss (P = .15). Tau expression was associated with ApoE epsilon4 in neither Ad nor Poss. Poss is genetically and histologically similar to Ad, although the overall A beta load is significantly increased in the latter. These findings support the recent Consensus Report's findings that all Alzheimer-type pathology may be significant.

Chen, M. and H. L. Fernandez (1999). "The Alzheimer's plaques, tangles and memory deficits may have a common origin. Part V: why is Ca2+ signal lower in the disease?" Front Biosci 4: A9-15.
The state of intracellular Ca2+ in aging and in Alzheimer's disease (AD) is a key but highly controversial issue and direct measurement of the Ca2+ fluctuations in the living human brain has not been possible thus far. We therefore further considered this issue from a theoretical perspective. Ca2+ signaling mediates many life processes including: fertilization, gene expression, cell division, growth and differentiation, muscle contraction, neurotransmission and memory formation. It is common observation that these Ca2+-mediated activities in human life are highest in young adulthood but diminish during aging, indicating that Ca2+ signaling potency (or intracellular Ca2+ levels) must be decreased in aging and AD. A potential explanation for this phenomenon could be that the Ca2+-mediated processes are also energy-dependent processes, because they all utilize the free energy reserve of the body for "useful" work, and it is known that Ca2+ gradient formation and Ca2+ movement across cell membrane are driven by energy-dependent systems. This intimate relationship between energy and Ca2+ signaling implies that the potency of Ca2+ signaling would be affected by changes of energy levels, which would necessarily decline in aging. These may underlie the deficit of Ca2+ signaling in the presymptomatic stage of AD. These considerations also support our view that Abeta and tau accumulation in AD is the result of inactivation of calcium-dependent enzymes, rather than overactivation of beta/(-secretases and some tau kinases. This is because most enzyme activities should be diminished, rather than overactivated, during aging. Furthermore, since energy/Ca2+ deficit is a natural event in aging, it follows that the accumulation of Abeta and tau would be initiated "spontaneously" as a result of "natural" aging, not necessarily by a "pathological" factor. Based on the analyses, we propose that intracellular Ca2+ deficit is most likely the primary and common cause (among the many contributing, secondary or individualized factors) for the plaque and tangle accumulation underlying sporadic AD. And we predict that this contention, though in contrast to many competing models, will be confirmed by the proposed experimentation in the future.

Cherin, P. (1999). "Treatment of inclusion body myositis." Curr Opin Rheumatol 11(6): 456-61.
Sporadic inclusion body myositis (s-IBM) is considered the most common muscle disease in patients older than 50 years, with a male predominance. Features of s-IBM include insidious onset, slowly and relentlessly progressive muscle weakness, a characteristic distribution and atrophy of both the proximal and distal muscle groups, and resistance to immunosuppressive drugs. The most characteristic pathologic feature is vacuolar degeneration of muscle fibers accompanied by intrafiber congophilia and clusters ("tangles") of paired-helical filaments, containing phosphorylated tau. The response of s-IBM to immunotherapy remains controversial. Some reports emphasized partial improvement in early stages of the disease. However, the lack of clear response to corticosteroids and immunosuppressive therapies, the deterioration of clinical strength despite suppression of inflammation but increasing number of fibers with vacuoles and amyloid deposits under therapy, and the accumulation of "Alzheimer-characteristic" proteins in vacuolated muscle fibers suggest that s-IBM may be a degenerative rather than an auto-immune inflammatory myopathy, and a secondary inflammation response.

Chou, K. C., K. D. Watenpaugh, et al. (1999). "A model of the complex between cyclin-dependent kinase 5 and the activation domain of neuronal Cdk5 activator." Biochem Biophys Res Commun 259(2): 420-8.
Tau protein kinase II (TPKII) is a heterodimer comprising a catalytic cyclin-dependent kinase subunit (Cdk5) and a regulatory protein called neuronal Cdk5 activator (Nck5a). TPKII is somewhat reminiscent, therefore, of the Cdk2-cyclin complex important in cell cycle regulation. In fact, although the amino acid sequence of Nck5a has little similarity to those of cyclins, recent experimental results obtained by site-directed mutagenesis studies have indicated that its activation domain, Nck5a*, may adopt a conformation of the cyclin-fold structure. Based on this structural inference, a 3-dimensional model of the Cdk5-Nck5a*-ATP complex was derived from the X-ray structure of Cdk2-cyclinA-ATP complex. The computed structure for TPKII is fully compatible with experimental data derived from studies of the Cdk5-Nck5a system, and also predicts which amino acid residues might be involved in formation of the Cdk5-Nck5a* interface and ATP binding pocket in TPKII. The computational structure also shows the interactive region of Nck5a* and the T-loop of Cdk5, a critical region in TPKII which functions as a gate-control-lever of the catalytic cleft. Furthermore, a physical mechanism is put forth to explain why the activation of TPKII is not dependent upon phosphorylation of the Cdk5 subunit, a puzzle long-standing in this area. These findings provide a model with which to consider design of compounds which might serve as inhibitors of TPKII.

Crawford, F., M. Freeman, et al. (1999). "No genetic association between polymorphisms in the Tau gene and Alzheimer's disease in clinic or population based samples." Neurosci Lett 266(3): 193-6.
Mutations in the tau protein gene have recently been found to cause familial fronto-temporal dementia in a number of kindreds demonstrating linkage to chromosome 17. Given that tau pathology is a hallmark of Alzheimer's disease (AD), this raises the possibility that mutations in tau may also be associated with AD. We have investigated the allelic frequencies of polymorphisms in the Tau gene for a possible allelic distortion in Alzheimer's cases, which might suggest a conferred genetic risk. We have genotyped 65 community-based and 200 clinic-based AD cases, and 142 community-based controls at the Tau exon 6 AflIII and BslI polymorphisms and find no independent association with risk for AD in these samples. Further analysis including APOE genotypes from the same samples demonstrated no interaction between either of these polymorphisms and APOE in conferring risk for AD. In addition, haplotype analysis across both sites revealed no difference in haplotype frequencies between cases and controls, nor any interaction with APOE. Therefore our data do not suggest any association between these variations in the Tau gene and Alzheimer's disease.

Culvenor, J. G., C. A. McLean, et al. (1999). "Non-Abeta component of Alzheimer's disease amyloid (NAC) revisited. NAC and alpha-synuclein are not associated with Abeta amyloid." Am J Pathol 155(4): 1173-81.
alpha-Synuclein (alphaSN), also termed the precursor of the non-Abeta component of Alzheimer's disease (AD) amyloid (NACP), is a major component of Lewy bodies and Lewy neurites pathognomonic of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). A fragment of alphaSN termed the non-Abeta component of AD amyloid (NAC) had previously been identified as a constituent of AD amyloid plaques. To clarify the relationship of NAC and alphaSN with Abeta plaques, antibodies were raised to three domains of alphaSN. All antibodies produced punctate labeling of human cortex and strong labeling of Lewy bodies. Using antibodies to alphaSN(75-91) to label cortical and hippocampal sections of pathologically proven AD cases, we found no evidence for NAC in Abeta amyloid plaques. Double labeling of tissue sections in mixed DLB/AD cases revealed alphaSN in dystrophic neuritic processes, some of which were in close association with Abeta plaques restricted to the CA1 hippocampal region. In brain homogenates alphaSN was predominantly recovered in the cytosolic fraction as a 16-kd protein on Western analysis; however, significant amounts of aggregated and alphaSN fragments were also found in urea extracts of SDS-insoluble material from DLB and PD cases. NAC antibodies identified an endogenous fragment of 6 kd in the cytosolic and urea-soluble brain fractions. This fragment may be produced as a consequence of alphaSN aggregation or alternatively may accelerate aggregation of the full-length alphaSN.

Delacourte, A. (1999). "Biochemical and molecular characterization of neurofibrillary degeneration in frontotemporal dementias." Dement Geriatr Cogn Disord 10 Suppl 1: 75-9.
Neurofibrillary degeneration (NFD) is a degenerating process characterized by the intraneuronal aggregation of abnormal tau proteins. These proteins have a biochemical signature which is disease-specific. They also have a neocortical distribution which is typical of the disease. Pathological tau proteins have been analyzed qualitatively and quantitatively in all diseases that may present the clinical symptoms of frontotemporal dementias. In Alzheimer's disease, a disease with sometimes a frontal predominance, paired helical filaments (PHF) of neurofibrillary tangles are made of hyperphosphorylated tau, named PHF-tau. Their electrophoretic profile consists of four main bands (tau 55, 64, 69, 74 kD), resulting from the presence of the six tau isoforms. In Pick's disease the phosphorylated tau from Pick bodies are made of two major components (tau 55, 64 kD) and a minor 69 kD resulting from the lack of tau isoforms with the translated exon 10 (E10-). Corticobasal degeneration (CBD) also has a different pattern of tau variants, with tau 64, 69 components and a minor tau 74. Pathological tau proteins that aggregate in CBD (and progressive supranuclear palsy) are exclusively made of E10+ tau isoforms. In frontotemporal dementias non-Alzheimer, non-Pick (Lund and Manchester criteria), we did not observe the presence of pathological tau proteins in 2 cases, but a third one presented a particular pattern of tau, with soluble pathological tau in frontotemporal areas. These data show that this group could be heterogeneous.In conclusion, the biochemical signature of tau distinguishes four classes of frontotemporal dementia. The characteristic tau phenotypes observed are linked to the specific neuronal networks that are affected in each disease.

Delacourte, A., J. P. David, et al. (1999). "The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease." Neurology 52(6): 1158-65.
OBJECTIVE: To determine the spatiotemporal mapping of neurofibrillary degeneration (NFD) in normal aging and the different stages of AD. BACKGROUND: The pathophysiologic significance of AD lesions, namely amyloid plaques and neurofibrillary tangles, is still unclear, especially their interrelationship and their link with cognitive impairment. METHODS: The study included 130 patients of various ages and different cognitive statuses, from nondemented control subjects (n = 60, prospective study) to patients with severe definite AD. Paired helical filaments (PHF)-tau and Abeta were used as biochemical and histologic markers of NFD and amyloid plaques, respectively. RESULTS: NFD with PHF-tau was systematically present in variable amounts in the hippocampal region of nondemented patients age >75 years. When NFD was found in other brain areas, it was always along a stereotyped, sequential, hierarchical pathway. The progression was categorized into 10 stages according to the brain regions affected: transentorhinal cortex (S1), entorhinal (S2), hippocampus (S3), anterior temporal cortex (S4), inferior temporal cortex (S5), medium temporal cortex (S6), polymodal association areas (prefrontal, parietal inferior, temporal superior) (S7), unimodal areas (S8), primary motor (S9a) or sensory (S9b, S9c) areas, and all neocortical areas (S10). Up to stage 6, the disease could be asymptomatic. In all cases studied here, stage 7 individuals with two polymodal association areas affected by tau pathologic states were cognitively impaired. CONCLUSIONS: The relationship between NFD and Alzheimer-type dementia, and the criteria for a biochemical diagnosis of AD, are documented, and an association between AD and the extent of NFD in defined brain areas is shown.

DeMattos, R. B., F. E. Thorngate, et al. (1999). "A test of the cytosolic apolipoprotein E hypothesis fails to detect the escape of apolipoprotein E from the endocytic pathway into the cytosol and shows that direct expression of apolipoprotein E in the cytosol is cytotoxic." J Neurosci 19(7): 2464-73.
Genetic evidence indicates that apolipoprotein E4 (apoE4) is a risk factor for the development of Alzheimer's disease. A controversial hypothesis proposes that apoE, a typical secretory protein, accesses the neuronal cytosol in which apoE3, but not apoE4, protects tau from hyperphosphorylation. However, no conclusive evidence for the presence of apoE in the cytosolic compartment has been presented. We designed a novel assay to test whether apoE can access the cytosol via escape from the endocytic pathway by incorporating a nuclear localization signal (NLS) into apoE. Control experiments demonstrated that apoE plus NLS (apoE+NLS) is chaperoned to the nucleus if it reaches the cytosolic compartment. When exogenous apoE+NLS was endocytosed by neuronal cells, no nuclear apoE was detected, indicating that apoE remains within the endocytic pathway and does not escape into the cytosol. Furthermore, we show that direct cytosolic expression of apoE is cytotoxic. These data argue that effects of apoE on the neuronal cytoskeleton and on neurite outgrowth are not mediated via cytosolic interactions but rather by actions originating at the cell surface.

Di Noto, L., M. A. DeTure, et al. (1999). "Disulfide-cross-linked tau and MAP2 homodimers readily promote microtubule assembly." Mol Cell Biol Res Commun 2(1): 71-6.
The neuronal proteins Tau and MAP2 use homologous C-terminal MT-binding regions (MTBRs) to interact with microtubules, F-actin, and intermediate filaments. Although Tau-MTBR is the principal component of pronase-treated Alzheimer paired helical filaments, both Tau and MAP2 form filaments in vitro from disulfide-linked homodimers. That the critical thiol lies within a domain needed for MT binding raised the question: Does disulfide formation block Tau-Tau or MAP2-MAP2 dimer binding to microtubules, thereby acting to divert dimers toward filament formation? We now report that cross-linked Tau and MAP2 homodimers readily promote tubulin polymerization and that monomer and dimer affinity for MTs is surprisingly similar. Therefore, disulfide cross-bridging into homodimers is unlikely to be a drive force for filament formation in Alzheimer's disease.

Dickson, D. W. (1999). "Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration." J Neurol 246 Suppl 2: II6-15.
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are usually sporadic multi-system degenerations associated with filamentous tau inclusions in neurons and glia. As such they can be considered sporadic tauopathies in contrast to familial tauopathies linked to mutations in the tau gene. Mutations have not been found in the tau gene in either PSP or CBD. The clinical syndromes and neuroimaging of typical cases of PSP and CBD are distinct; however, atypical cases are described that have overlapping clinical and pathologic features. Both PSP and CBD have similar biochemical alterations in the tau protein, with the abnormal tau protein containing predominantly four-repeat tau. While there is overlap in the pathology in PSP and CBD, there are sufficient differences to continue the present day trend to consider these separate disorders. Several important pathologic features differentiate PSP from CBD. Ballooned neurons are frequent and nearly a sine qua non for CBD, but they are found in PSP at a frequency similar to that of other neurodegenerative diseases, such as Alzheimer's disease. Astrocytic lesions are different, with tufted astrocytes found in motor cortex and striatum in PSP and astrocytic plaques in focal atrophic cortices in CBD. The most characteristic neuronal tau pathology in CBD is wispy, fine filamentous inclusions within neuronal cell bodies, while affected neurons in PSP have compact, dense filamentous aggregates characteristic of globose neurofibrillary tangles. Thread-like processes in gray and white matter are much more numerous and widespread in CBD than in PSP. The brunt of the pathology in CBD is in the cerebrum, while the basal ganglia, diencephalon and brainstem are the targets of PSP. Further clinicopathologic studies will refine our understanding of these disorders and open the possibility that common etiologic factors may be identified for these unusual sporadic tauopathies.

Dickson, T. C., C. E. King, et al. (1999). "Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer's disease." Exp Neurol 156(1): 100-10.
We examined the neurochemical and morphological diversity of abnormal neurites associated with beta-amyloid plaque formation in the early and late stages of Alzheimer's disease. Preclinical Alzheimer's disease was characterised by the presence of abnormal neurites containing either neurofilament or chromogranin A immunoreactivity. All clustered dystrophic neurites in these cases were associated with beta-amyloid plaques. Neurofilament immunoreactive dystrophic neurites in preclinical Alzheimer's disease could be further subclassified into bulb- and ring-like structures, and these abnormal neurites contained both phosphorylated and dephosphorylated neurofilament epitopes. Dystrophic neurites in Alzheimer's disease could be subdivided into predominantly neurofilament, tau, or chromogranin A immunolabeled forms. Some neurofilament immunoreactive neurites had a core region labeled for tau. The neurofilaments of the dystrophic neurites in Alzheimer's disease had the same complement of phosphorylation- and dephosphorylation-dependent epitopes as observed in preclinical cases. Therefore, an abnormal accumulation of variably phosphorylated neurofilaments represent the earliest cytoskeletal alteration associated with dystrophic neurite formation. Furthermore, these data indicate that dystrophic neurites may "mature" through neurofilament-abundant forms to the neurites containing the profoundly altered filaments labeled for tau. The precise morphological and neurochemical changes associated with dystrophic neurite formation suggests that beta-amyloid plaques are causing physical damage to surrounding axons. The resultant axonal sprouting and profound cytoskeletal alterations would follow the chronic stimulation of the stereotypical reaction to such physical trauma.

Durany, N., G. Munch, et al. (1999). "Investigations on oxidative stress and therapeutical implications in dementia." Eur Arch Psychiatry Clin Neurosci 249 Suppl 3: 68-73.
Alzheimer's disease (AD) is a progressive dementia affecting a large proportion of the aging population. The histopathological changes in AD include neuronal cell death and formation of amyloid plaques and neurofibrillary tangles (NFTs) NFTs are composed of hyperphosphorylated tau protein, and senile plaques contain aggregates of the beta-peptide. There is also evidence that brain tissue in patients with AD is exposed to oxidative stress during the course of the disease. Advanced glycation endproducts (AGEs), which are formed by a non-enzymatic reaction of glucose with long-lived protein deposits, are potentially toxic to the cell, are present in brain plaques in AD, and its extracellular accumulation in AD may be caused by an accelerated oxidation of glycated proteins. The microtubuli-associated protein tau is also subject to intracellular AGE formation. AGEs participate in neuronal death causing direct (chemical) radical production: Glycated proteins produce nearly 50-fold more radicals than non-glycated proteins, and indirect (cellular) radical production: Interaction of AGEs with cells increases oxidative stress. During aging cellular defence mechanisms weaken and the damages to cell constituents accumulate leading to loss of function and finally cell death. The development of drugs for the treatment of AD remains at a very unsatisfying state. However, pharmacological approaches which break the vicious cycles of oxidative stress and neurodegeneration offer new opportunities for the treatment of AD. Theses approaches include AGE-inhibitors, antioxidants, and anti-inflammatory substances, which prevent radical production. AGE inhibitors might be able to stop formation of AGE-modified beta-amyloid deposits, antioxidants are likely to scavenge intracellular and extracellular superoxide radicals and hydrogen peroxide before these radicals damage cell constituents or activate microglia, and anti-inflammatory drugs attenuating microglial radical and cytokine production.

Duyckaerts, C., M. A. Colle, et al. (1999). "[Alzheimer's disease: lesions and their progression]." Rev Neurol (Paris) 155 Suppl 4: S17-27.
Alzheimer disease appears to be a stereotyped mode of reaction of the central nervous system to various types of aggression such as different mutations involving various proteins, trisomy 21 or repeated head trauma as in dementia pugilistica. Rather than a disease, it appears to be a clinicopathological syndrome due to various causes. Lesions may be considered under 3 headings: neurofibrillary pathology, A beta peptide deposits and loss (neuronal and synaptic). Neurofibrillary pathology includes the neurofibrillary tangle, the crown of the senile plaque and the neuropil threads. All those lesions are characterized by the same ultrastructure--i.e. the accumulation of paired helical filaments--and the same immunohistochemistry: they are labelled by antibodies directed against the tau proteins. The amyloid deposits, present in the core of the senile plaque and in the vascular walls, are made of a 40 to 42 amino-acids long peptide, named A beta, derived from the amyloid precursor protein (APP). Antibodies directed against the A beta peptide also label diffuse deposits that are devoid of the tinctorial affinities and of the biochemical properties of amyloid substances. Those diffuse deposits are insufficient to cause dementia since they may be observed in high density in aged people without intellectual deterioration. Neuronal loss occurs after neurofibrillary pathology. The role of the synaptic pathology remains discussed. Besides tau proteins, A beta peptide and APP, several other proteins may play an important role: apolipoprotein E which could act as a chaperone protein, inducing or facilitating the formation of amyloid, presenilins 1 and 2, mutated in some cases of familial Alzheimer disease, alpha-synuclein which is present in the Lewy bodies found in Parkinson disease and in dementia with Lewy bodies. The A beta deposits are diffusely distributed in the cerebral cortex; the neurofibrillary changes have a hierarchical distribution. The progression of the neurofibrillary pathology in the various cortical areas follow a stereotyped sequence that may help to grade the severity of the disease. Progression may take decades. The relations between aging and Alzheimer disease are still poorly understood. Frequency of Alzheimer type lesions in old people could suggest that they are the inevitable burden of age, but this has been discussed.

Ekinci, F. J., K. U. Malik, et al. (1999). "Activation of the L voltage-sensitive calcium channel by mitogen-activated protein (MAP) kinase following exposure of neuronal cells to beta-amyloid. MAP kinase mediates beta-amyloid-induced neurodegeneration." J Biol Chem 274(42): 30322-7.
Neuronal degeneration in Alzheimer's disease (AD) has been variously attributed to increases in cytosolic calcium, reactive oxygen species, and phosphorylated forms of the microtubule-associated protein tau. beta-Amyloid (betaA), which accumulates extracellularly in AD brain, induces calcium influx in culture via the L voltage-sensitive calcium channel. Since this channel is normally activated by protein kinase A-mediated phosphorylation, we examined kinase activities recruited following betaA treatment of cortical neurons and SH-SY-5Y neuroblastoma. betaA increased channel phosphorylation; this increase was unaffected by the protein kinase A inhibitor H89 but was reduced by the mitogen-activated protein (MAP) kinase inhibitor PD98059. Pharmacological and antisense oligonucleotide-mediated reduction of MAP kinase activity also reduced betaA-induced accumulation of calcium, reactive oxygen species, phospho-tau immunoreactivity, and apoptosis. These findings indicate that MAP kinase mediates multiple aspects of betaA-induced neurotoxicity and indicates that calcium influx initiates neurodegeneration in AD. betaA increased MAP kinase-mediated phosphorylation of membrane-associated proteins and reduced phosphorylation of cytosolic proteins without increasing overall MAP kinase activity. Increasing MAP kinase activity with epidermal growth factor did not increase channel phosphorylation. These findings indicate that redirection, rather than increased activation, of MAP kinase activity mediates betaA-induced neurotoxicity.

Ekinci, F. J. and T. B. Shea (1999). "Hyperactivation of mitogen-activated protein kinase increases phospho-tau immunoreactivity within human neuroblastoma: additive and synergistic influence of alteration of additional kinase activities." Cell Mol Neurobiol 19(2): 249-60.
Mitogen-activated protein (MAP) kinase phosphorylates tau in cell-free analyses, but whether or not it does so within intact cells remains controversial. In the present study, microinjection of MAP kinase into SH-SY-5Y human neuroblastoma cells increased tau immunoreactivity toward the phosphodependent antibodies PHF-1 and AT-8. In contrast, treatment with a specific inhibitor of MAP kinase (PD98059) did not diminish "basal" levels of these immunoreactivities in otherwise untreated cells. These findings indicate that hyperactivation of MAP kinase increases phospho-tau levels within cells, despite that MAP kinase apparently does not substantially influence intracellular tau phosphorylation under normal conditions. These findings underscore that results obtained following inhibition of kinase activities do not necessarily provide an indication of the consequences accompanying hyperactivation of that same kinase. Several studies conducted in cell-free systems indicate that exposure of tau to multiple kinases can have synergistic effects on the nature and extent of tau phosphorylation. We therefore examined whether or not such effects could be demonstrated within these cells. Site-specific phospho-tau immunoreactivity was increased in additive and synergistic manners by treatment of injected cells with TPA (which activates PKC), calcium ionophore (which activates calcium-dependent kinases), and wortmannin (which inhibits PIP3 kinase). Alteration in total tau levels was insufficient to account for the full extent of the increase in phospho-tau immunoreactivity. These additional results indicate that multiple kinase activities modulate the influence of MAP kinase on tau within intact cells.

Esclaire, F., G. Kisby, et al. (1999). "The Guam cycad toxin methylazoxymethanol damages neuronal DNA and modulates tau mRNA expression and excitotoxicity." Exp Neurol 155(1): 11-21.
As in Alzheimer's disease, brains of Guam Chamorros with amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) contain intraneuronal-paired helical filaments composed of accumulated phosphorylated tau protein. Tau mRNA expression in rat neuronal cultures-normally modulated by glutamate-increases after treatment with the aglycone of cycasin, a cycad-derived toxin whose concentration in Chamorro food varies with disease incidence. Elevated Tau gene expression in vitro is coincident with increased cycasin-related DNA adducts and reduced DNA repair. Cycasin and endogenous glutamate may together promote the accumulation of tau protein and neuronal degeneration in Western Pacific ALS/PDC.

Ezquerra, M., P. Pastor, et al. (1999). "Identification of a novel polymorphism in the promoter region of the tau gene highly associated to progressive supranuclear palsy in humans." Neurosci Lett 275(3): 183-6.
An intronic polymorphism and other changes in the transcribed region of the tau gene forming a haplotype have been previously described associated to progressive supranuclear palsy (PSP). These results raised the possibility that a change at or near the tau gene could be responsible for an increased risk to develop PSP. We initiated the present work in research for potential changes in the promoter region of the tau gene that could further extend the previously described haplotype. The tau promoter region was analyzed through single strand conformation polymorphism followed by direct sequencing in PSP patients (n = 35), in controls (n = 195) and in Alzheimer's disease (AD; n = 74) patients. We have been able to identify a G to C change at position -221 of the tau gene promoter region. The CC genotype has been detected to be present with a significantly higher frequency in PSP patients (91.4%; P < 0.00001; OR = 11.8), but not in AD patients, as compared with controls (49.74%). Subsequently we have detected that the CC -221 tau promoter genotype is significantly associated to the tau intronic A0/A0 genotype (P < 0.00001). The detected -221 tau G to C change occurs within a potential c-myb proto-oncogene element present in the promoter region. Thus, in addition to extending the previously described haplotype associated to PSP, this -221 G to C change is an interesting candidate that could provide a potential explanation for the association of the haplotype to increased risk for developing PSP.

Farrer, M., K. Gwinn-Hardy, et al. (1999). "The genetics of disorders with synuclein pathology and parkinsonism." Hum Mol Genet 8(10): 1901-5.
Despite being considered the archetypal non-genetic neurological disorder, genetic analysis of Parkinson's disease has shown that there are at least three genetic loci. Furthermore, these analyses have suggested that the phenotype of the pathogenic loci is wider than simple Parkinson's disease and may include Lewy body dementia and some forms of essential tremor. Identification of alpha-synuclein as the first of the loci involved in Parkinson's disease and the identification of this protein in pathological deposits in other disorders has led to the suggestion that it may share pathogenic mechanisms with multiple system atrophy, Alzheimer's disease and prion disease and that these mechanisms are related to a synuclein pathway to cell death. Finally, genetic analysis of the synuclein diseases and the tau diseases may indicate that this synuclein pathway is an alternative to the tau pathway to cell death.

Felician, O. and T. A. Sandson (1999). "The neurobiology and pharmacotherapy of Alzheimer's disease." J Neuropsychiatry Clin Neurosci 11(1): 19-31.
Alzheimer's disease (AD), the most common cause of dementia, has become a major public health concern as our population ages. In recent years, AD has attracted the attention of a wide range of biological disciplines, and substantial progress has been made in understanding the mechanisms of neurodegeneration in AD. Four different genes have now been associated with AD and are providing insights into the pathogenesis of the disease. The roles of beta-amyloid, tau, hormonal changes, inflammation, and oxidative stress in the neurodegeneration of AD are also being delineated. Based on these discoveries, rational therapeutic strategies are developing rapidly. The authors review these and other recent advances in the neurobiology and pharmacotherapy of AD.

Ferrer, I., C. Marin, et al. (1999). "BDNF and full-length and truncated TrkB expression in Alzheimer disease. Implications in therapeutic strategies." J Neuropathol Exp Neurol 58(7): 729-39.
Brain-derived neurotrophic factor (BDNF), and full-length and truncated tyrosin kinase B receptor (TrkB) protein expression were examined by Western blotting and immunohistochemistry in the frontal cortex and hippocampus of individuals affected by long-lasting severe Alzheimer disease (AD) and age-matched controls. Since preliminary processing studies in the brains of rats have shown loss of immunoreactivity depending on the postmortem delay in tissue processing and on the type, duration, and temperature of the fixative solution, only human samples obtained up to 6 hours (h) after death for biochemical and morphological studies and fixed by immersion in 4% paraformaldehyde for 24 h for morphological studies were included in the present series. Decreased BDNF and full-length TrkB expression accompanied by increased truncated TrkB expression, as revealed by Western blotting, was observed in the frontal cortex of patients with AD. Immunohistochemistry disclosed reduced BDNF and full-length TrkB immunoreactivity in neurons. BDNF decrease was equally observed in tangle-bearing and non-tangle-bearing neurons, as revealed with double-labeling immunohistochemistry to BDNF and phosphorylated tau or phosphorylated neurofilament epitopes. Full-length TrkB immunoreactivity was largely decreased in tangle-bearing neurons, whereas only moderate decreases occurred in neurons with granulovacuolar degeneration. Strong BDNF immunoreactivity was observed in dystrophic neurites surrounding senile plaques, whereas strong TrkB expression occurred in reactive glial cells, including those surrounding senile plaques. Finally, truncated TrkB immunoreactivity was observed in individual neurons and in reactive glial cells in the cerebral cortex and white matter in AD. These results show decay in the expression of BDNF and TrkB in AD neurons, accompanied by altered BDNF, and full-length and truncated TrkB expression in dystrophic neurites and reactive glial cells, respectively, in this disease. The present results demonstrate selective decline of the BDNF/TrkB neurotrophic signaling pathway in the frontal cortex and hippocampus in AD and provide supplemental data that may be relevant in discussing the suitability of the use of BDNF as a therapeutic agent in patients with AD.

Fladby, T. and J. Maehlen (1999). "[The amyloid and tau hypothesis in degenerative dementia]." Tidsskr Nor Laegeforen 119(7): 976-9.
Alzheimer's disease is the major cause of dementia. The neuropathological basis for the diagnosis is the presence of senile plaques and neurofibrillary degeneration in brain tissue. Senile plaques consist of a central core of fibrillar amyloid beta-protein and some other proteins, surrounded by swollen neurites. Three genes causing early-onset autosomal dominant Alzheimer have so far been described. Recently, polymorphisms in three other genes have been shown to influence the risk for late-onset Alzheimer's disease. All these genes seem to influence the metabolization of the beta-protein or the precursor for this protein. These findings support the "amyloid hypothesis" which states that toxic effects of beta-protein cause Alzheimer's disease. Frontotemporal dementias are the second most common types of degenerative dementias, and may account for more than 10% of the dementias. A substantial number of these cases are probably caused by a mutation in the gene for tau protein on chromosome 17.

Flaherty, D., Q. Lu, et al. (1999). "Regulation of tau phosphorylation in microtubule fractions by apolipoprotein E." J Neurosci Res 56(3): 271-4.
In Alzheimer's disease (AD), a family of proteins collectively named tau are displaced from their normal association with microtubules and are found in in a hyperphosphorylated state deposited into paired helical filaments (PHFs). PHFs are the hallmark cytoskeletal pathology of the disease, and the degree of PHF pathology correlates with the clinical severity of AD. Certain apolipoprotein E (apoE) isoforms have been identified as either risk or protective factors for AD, and one of the proposed mechanisms involves an interaction and potentially modulatory effects on tau hyperphosphorylation by the different apoE isoforms. In these studies, we directly tested the effects of apoE, E2, E3, and E4 on AD-like phosphorylation of tau in brain microtubule fractions. We found that apoE attenuates tau hyperphosphorylation in the fractions, but the pattern was indistinguishable for the different isoforms.

Frappier, T., N. S. Liang, et al. (1999). "Abnormal microtubule packing in processes of SF9 cells expressing the FTDP-17 V337M tau mutation." FEBS Lett 455(3): 262-6.
Mutations in the gene for the microtubule associated protein, tau have been identified for fronto-temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). In vitro data have shown that FTDP-17 mutant tau proteins have a reduced ability to bind microtubules and to promote microtubule assembly. Using the baculovirus system we have examined the effect of the V337M mutation on the organization of the microtubules at the ultrastructural level. Our results show that the organization of the microtubules is disrupted in the presence of V337M tau with greater distances between the microtubules and fewer microtubules per process.

Gartner, U., M. Holzer, et al. (1999). "Elevated expression of p21ras is an early event in Alzheimer's disease and precedes neurofibrillary degeneration." Neuroscience 91(1): 1-5.
Alzheimer's disease is a chronic degenerative disorder characterized by the intracellular accumulation of "paired helical filaments" consisting of highly phosphorylated tau and by extracellular deposits of aggregated Abeta-peptide. Furthermore, neurodegeneration in Alzheimer's disease is associated with the appearance of neuritic growth profiles that are aberrant with respect to their localization, morphological appearance, and composition of cytoskeletal elements. During early stages of Alzheimer's disease, a variety of growth factors and mitogenic compounds are elevated. Most of these factors mediate their cellular effects through activation of the p21ras-dependent mitogen-activated protein kinase cascade, a pathway that is also involved in the regulation of expression and post-translational modification of the amyloid precursor protein and tau protein. We previously reported on the elevated expression of p21ras associated with paired helical filament formation and Abeta-deposits. However, the question arises as to whether induction of p21ras and the downstream mitogen-activated protein kinase cascade is an early event with rather primary importance in the pathogenetic chain or simply occurs as a cellular response to neurodegeneration. The present study shows that expression of p21ras is clearly elevated in very early stages of the disease, preceding both neurofibrillary pathology and formation of Abeta.

Garver, T. D., R. L. Kincaid, et al. (1999). "Reduction of calcineurin activity in brain by antisense oligonucleotides leads to persistent phosphorylation of tau protein at Thr181 and Thr231." Mol Pharmacol 55(4): 632-41.
Phosphorylation of tau protein promotes stability of the axonal cytoskeleton; aberrant tau phosphorylation is implicated in the biogenesis of paired helical filaments (PHF) seen in Alzheimer's disease. Protein kinases and phosphatases that modulate tau phosphorylation have been identified using in vitro techniques; however, the role of these enzymes in vivo has not been determined. We used intraventricular infusions of antisense oligodeoxynucleotides (ODNs) directed against the major brain isoforms of the Ca2+/calmodulin-dependent phosphatase calcineurin to determine how reduced activity of this enzyme would affect tau dephosphorylation. Five-day infusions of antisense ODNs (5 and 10 nmol/day) in rats decreased immunoreactive levels and activity of calcineurin throughout the brain; sense ODNs, scrambled ODNs, and infusion vehicle alone had no effect. When neocortical slices were prepared from antisense ODN-treated rats and incubated for 1 to 2 h in vitro, tau protein remained phosphorylated as determined by using the phosphorylation-sensitive monoclonal antibodies AT-180 (Thr231) and AT-270 (Thr181). In contrast, AT-180 and AT-270 sites were completely dephosphorylated during incubation of neocortical slices from vehicle-infused controls and sense ODN-treated rats. Neocortical slices from antisense-treated rats were incubated with the phosphatase inhibitors okadaic acid (100 nM; 10 microM) and FK-520 (5 microM); these preparations showed enhanced tau phosphorylation, consistent with a significant loss of calcineurin activity. Thus, we conclude that phosphorylation of at least two sites on tau protein, namely, Thr181 and Thr231, is regulated by calcineurin.

Gearing, M., M. Lynn, et al. (1999). "Neurofibrillary pathology in Alzheimer disease with Lewy bodies: two subgroups." Arch Neurol 56(2): 203-8.
BACKGROUND: While NFT frequency is reportedly reduced in AD+DLB, we often encounter abundant neocortical NFTs in such cases and decided to investigate this discrepancy. OBJECTIVE: To compare neurofibrillary tangle (NFT) frequency in Alzheimer disease with concomitant dementia with Lewy bodies (AD+DLB) with NFT frequency in "pure" AD. METHODS: Neurofibrillary tangle frequency, as well as regional staging of neurofibrillary degeneration modified from Braak, was scored in 160 autopsy cases of primary dementia (80 AD+DLB cases and 80 pure AD cases). RESULTS: Neurofibrillary tangle and modified Braak scores were lower in AD+DLB, as reported previously. Yet, neocortical NFT scores assumed markedly different patterns in the 2 groups (P = .001). In pure AD, NFT scores of "frequent" were predominant: more cases exhibited frequent than moderate or sparse NFTs. In AD+DLB, the distribution of NFT scores was bimodal: NFTs were either frequent or few to absent. Neocortical NFT scores in the AD+DLB group tended to parallel the severity of other types of tau cytopathology (neuropil threads and tau-positive plaque neurites). CONCLUSIONS: Cases of AD+DLB may be divided into 2 subgroups based on the extent of neocortical neurofibrillary pathology. These findings could have implications for disease pathogenesis and treatment.

Geddes, J. F., G. H. Vowles, et al. (1999). "Neuronal cytoskeletal changes are an early consequence of repetitive head injury." Acta Neuropathol (Berl) 98(2): 171-8.
While neuropathological studies have established the pathology of dementia pugilistica to be similar to that of Alzheimer's disease, there is little information about the early histological changes caused by the repetitive trauma that eventually produces dementia pugilistica. We have examined the brains of four young men and a frontal lobectomy specimen from a fifth, age range 23-28 years, all of whom suffered mild chronic head injury. There were two boxers, a footballer, a mentally subnormal man with a long history of head banging, and an epileptic patient who repeatedly hit his head during seizures. The four autopsy cases were widely sampled; the lobectomy specimen was serially sliced after fixation. Routine stains were performed; inmmunostaining included beta-amyloid precursor protein, amyloid beta-protein (Abeta), tau and apolipoprotein E (apoE). Pathological findings in all five cases were of neocortical neurofibrillary tangles (NFTs) and neuropil threads, with groups of tangles consistently situated around blood vessels in the worst affected regions. No Abeta immunoreactivity was detected. The amount of neuronal apoE expression varied widely between the cases with no clear relation to the NFTs. The apoE genotype was determined in only two cases (both epsilon3/epsilon3). It appears that repetitive head injury in young adults is initially associated with neocortical NFT formation in the absence of Abeta deposition. The distribution of the tau pathology suggests that the pathogenesis of cytoskeletal abnormalities may involve damage to blood vessels or perivascular elements.

Ghoshal, N., J. F. Smiley, et al. (1999). "A new molecular link between the fibrillar and granulovacuolar lesions of Alzheimer's disease." Am J Pathol 155(4): 1163-72.
Alzheimer's Disease (AD) is a progressive neurodegenerative disorder involving select neurons of the hippocampus, neocortex, and other regions of the brain. Markers of end stage disease include fibrillar lesions, which accumulate hyperphosphorylated tau protein polymerized into filaments, and granulovacuolar lesions, which appear primarily within the hippocampus. The mechanism by which only select populations of neurons develop these lesions as well as the relationship between them is unknown. To address these questions, we have turned to AD tissue to search for enzymes specifically involved in tau hyperphosphorylation. Recently, we showed that the principal phosphotransferases associated with AD brain-derived tau filaments are members of the casein kinase-1 (CK1) family of protein kinases. Here we report the distribution of three CK1 isoforms (Ckialpha, Ckidelta, and Ckiepsilon) in AD and control brains using immunohistochemistry and Western analysis. In addition to colocalizing with elements of the fibrillar pathology, CK1 is found within the matrix of granulovacuolar degeneration bodies. Furthermore, levels of all CK1 isoforms are elevated in the CA1 region of AD hippocampus relative to controls, with one isoform, Ckidelta, being elevated >30-fold. We propose that overexpression of this protein kinase family plays a key role in the hyperphosphorylation of tau and in the formation of AD-related pathology.

Ginsberg, S. D., J. E. Galvin, et al. (1999). "Accumulation of intracellular amyloid-beta peptide (A beta 1-40) in mucopolysaccharidosis brains." J Neuropathol Exp Neurol 58(8): 815-24.
To evaluate whether in vivo accumulations of heparan sulfate caused by inborn errors in the metabolism of glycosaminoglycans lead to the formation of neurofibrillary tangles and/or senile plaques, as seen in Alzheimer disease (AD), we studied postmortem brains from 9 patients, ages 1 to 42 years, with mucopolysaccharidosis (MPS). The brains of patients with Hurler's syndrome (MPS I: n = 5) and Sanfilippo's syndrome (MPS III; n = 4) as well as from caprine MPS IIID and murine MPS VII models were evaluated by thioflavine-S staining and by immunohistochemistry using antibodies directed against heparan sulfate proteoglycans, hyperphosphorylated tau, amyloid-beta peptide precursor proteins (APP), and amyloid-beta peptides (A beta [1-40], and A beta [1-42]). A two-site sandwich enzyme-linked immunosorbent assay (ELISA) was also utilized to compare levels of total soluble and insoluble A beta (1-40) and A beta (1-42) obtained from temporal cortex of MPS patients. Although no neurofibrillary tangles, senile plaques, or tau-positive lesions were detected in any of the MPS brains studied here, antibodies directed against A beta (1-40) intensely and diffusely stained the cytoplasm of cells throughout the brains of the MPS patients and the caprine MPS model. The ELISA assay also demonstrated a significant 3-fold increase in the level of soluble A beta (1-40) in the MPS brains compared with normal control brains. Thus, at least some of the metabolic defects that lead to accumulations of glycosaminoglycans in MPS also are associated with an increase in immunoreactive A beta (1-40) within the cytoplasmic compartment where they could contribute to the dysfunction and death of affected cells in these disorders, but not induce the formation of plaques and tangles. Models of MPS may enable mechanistic studies of the role A beta and glycosaminoglycans play in the amyloidosis that is a neuropathological feature of AD.

Goedert, M. and A. Klug (1999). "Tau protein and the paired helical filament of Alzheimer's disease." Brain Res Bull 50(5-6): 469-70.

Goedert, M. (1999). "Filamentous nerve cell inclusions in neurodegenerative diseases: tauopathies and alpha-synucleinopathies." Philos Trans R Soc Lond B Biol Sci 354(1386): 1101-18.
Alzheimer's disease and Parkinson's disease are the most common neurodegenerative diseases. They are characterized by the degeneration of selected populations of nerve cells that develop filamentous inclusions before degeneration. The neuronal inclusions of Alzheimer's disease are made of the microtubule-associated protein tau, in a hyperphosphorylated state. Recent work has shown that the filamentous inclusions of Parkinson's disease are made of the protein alpha-synuclein and that rare, familial forms of Parkinson's disease are caused by missense mutations in the alpha-synuclein gene. Besides Parkinson's disease, the filamentous inclusions of two additional neurodegenerative diseases, namely dementia with Lewy bodies and multiple system atrophy, have also been found to be made of alpha-synuclein. Abundant filamentous tau inclusions are not limited to Alzheimer's disease. They are the defining neuropathological characteristic of frontotemporal dementias such as Pick's disease, and of progressive supranuclear palsy and corticobasal degeneration. The recent discovery of mutations in the tau gene in familial forms of frontotemporal dementia has provided a direct link between tau dysfunction and dementing disease. The new work has established that tauopathies and alpha-synucleinopathies account for most late-onset neurodegenerative diseases in man. The formation of intracellular filamentous inclusions might be the gain of toxic function that leads to the demise of affected brain cells.

Goedert, M. (1999). "Alzheimer's disease. Pinning down phosphorylated tau." Nature 399(6738): 739-40.

Gozes, I., O. Perl, et al. (1999). "Mapping the active site in vasoactive intestinal peptide to a core of four amino acids: neuroprotective drug design." Proc Natl Acad Sci U S A 96(7): 4143-8.
The understanding of the molecular mechanisms leading to peptide action entails the identification of a core active site. The major 28-aa neuropeptide, vasoactive intestinal peptide (VIP), provides neuroprotection. A lipophilic derivative with a stearyl moiety at the N-terminal and norleucine residue replacing the Met-17 was 100-fold more potent than VIP in promoting neuronal survival, acting at femtomolar-picomolar concentration. To identify the active site in VIP, over 50 related fragments containing an N-terminal stearic acid attachment and an amidated C terminus were designed, synthesized, and tested for neuroprotective properties. Stearyl-Lys-Lys-Tyr-Leu-NH2 (derived from the C terminus of VIP and the related peptide, pituitary adenylate cyclase activating peptide) captured the neurotrophic effects offered by the entire 28-aa parent lipophilic derivative and protected against beta-amyloid toxicity in vitro. Furthermore, the 4-aa lipophilic peptide recognized VIP-binding sites and enhanced choline acetyltransferase activity as well as cognitive functions in Alzheimer's disease-related in vivo models. Biodistribution studies following intranasal administration of radiolabeled peptide demonstrated intact peptide in the brain 30 min after administration. Thus, lipophilic peptide fragments offer bioavailability and stability, providing lead compounds for drug design against neurodegenerative diseases.

Grant, S. M., A. Morinville, et al. (1999). "Phosphorylation of mitogen-activated protein kinase is altered in neuroectodermal cells overexpressing the human amyloid precursor protein 751 isoform." Brain Res Mol Brain Res 72(2): 115-20.
The aberrant expression or processing of the amyloid precursor protein (APP) is the only known genetic basis for presenile familial Alzheimer's disease, and the molecular connection between APP and tau has been perplexing. Attention has focused on proline-directed serine/threonine kinases as mediating the cytoskeletal modifications of Alzheimer's disease, and we show that overexpression of APP can influence the activation of a candidate kinase, the mitogen-activated protein kinase (MAPK). In murine embryonal carcinoma cells stably transfected with the human 751 isoform of APP, we observed steady-state hyperactivation of p42(MAPK) concomitant with APP overexpression 3 days after neuroectodermal differentiation. In more mature differentiated cells, immunocytochemical analysis revealed enhanced basal somatic and nuclear immunoreactivity for phosphorylated MAPK coupled with an attenuated phosphorylation response to growth factor stimulation. Our results suggest that APP can influence the MAPK signaling pathway in such a way that the absolute and time-dependent activation required for discrimination of the appropriate downstream response are compromised. Such an effect would have important consequences for the functioning of cells coincidentally expressing both proteins, a situation that occurs in neuronal populations vulnerable to Alzheimer's disease pathology.

Green, A. J., R. J. Harvey, et al. (1999). "Increased tau in the cerebrospinal fluid of patients with frontotemporal dementia and Alzheimer's disease." Neurosci Lett 259(2): 133-5.
Cerebrospinal fluid (CSF) concentrations of tau protein were measured using an enzyme-linked immunosorbent assay which measures both normal and hyperphosphorylated tau. Levels of CSF tau were measured in 17 patients with Alzheimer's disease and 23 patients with frontotemporal dementia, and were compared to age-matched healthy controls. The CSF tau concentration in control subjects was 198+/-49 pg/ml and no relationship was found between age and CSF tau concentrations in these subjects. CSF tau concentrations were significantly raised in patients with both Alzheimer's disease and frontotemporal dementia when compared to healthy controls (802+/-381 pg/ml, P<0.001; 612+/-382 pg/ml, P<0.05, respectively). In neither disease did CSF tau correlate with disease severity as assessed by the Mini Mental State Examination score (MMSE). This study shows that CSF tau is significantly raised in patients with frontotemporal dementia.

Grober, E., D. Dickson, et al. (1999). "Memory and mental status correlates of modified Braak staging." Neurobiol Aging 20(6): 573-9.
We assessed the relationships of performance on memory and mental status tests and neuropathologic stage of Alzheimer's disease as defined by Braak and Braak in 29 patients from a prospective clinicopathologic series. We predicted that memory changes would occur at an earlier Braak stage than mental status changes. Staging was accomplished by matching the topographic distribution of neurofibrillary lesions detected with tau immunocytochemistry to the best fitting diagram published by Braak and Braak. Higher Braak stages were associated with decrements in performance on both memory and mental status tests. As predicted, memory performance declined from stages II to III and mental status did not decline until stages III to IV. The association between memory and Braak stage was unchanged after adjusting for neocortical senile plaques, whereas adjustments for Braak stage eliminated the association between cognitive functioning and amyloid burden. We conclude that Braak staging provides a useful summary of Alzheimer's disease neuropathology, which is associated with both memory and mental status performance.

Grundke-Iqbal, I. and K. Iqbal (1999). "Tau pathology generated by overexpression of tau." Am J Pathol 155(6): 1781-5.

Guenette, S. Y. and R. E. Tanzi (1999). "Progress toward valid transgenic mouse models for Alzheimer's disease." Neurobiol Aging 20(2): 201-11.
A transgenic mouse model for Alzheimer's disease (AD) should mimic the age-dependent accumulation of beta-amyloid plaques, neurofibrillary tangles, neuronal cell death as well as display memory loss and behavioral deficits. Age-dependent accumulation of A beta deposits in mouse brain has been achieved in mice overexpressing mutant alleles of the amyloid precursor protein (APP). In contrast, mice bearing mutant alleles of the presenilin genes show increased production of the A beta42 peptide, but do not form amyloid deposits unless mutant alleles of APP are also overproduced. Furthermore, the onset of A beta deposition is greatly accelerated, paralleling the involvement of presenilins in early onset AD. Studies of APP and presenilin transgenic mice have shown 1) the absence of a requirement for a maturation step in dense core plaque formation, 2) evidence that beta-amyloid deposition is directed by regional factors, and 3) behavioral deficits are observed before A beta deposition. Crosses of APP transgenic mice with mice modified for known AD risk factors and "humanizing" the mouse may be necessary for complete replication of AD.

Haass, C. and E. Mandelkow (1999). "Proteolysis by presenilins and the renaissance of tau." Trends Cell Biol 9(6): 241-4.

Hall, G. F. (1999). "PHF-Tau from Alzheimer Brain is Rapidly Dephosphorylated and Degraded When Injected into Neurons in situ." J Alzheimers Dis 1(6): 379-386.
Accumulation of abnormally modified tau protein (PHF-tau) is the principal intracellular lesion in a variety of neurodegenerative diseases, including Alzheimer's Disease (AD), but the cellular mechanisms underlying this accumulation are unknown. In this study, the cellular metabolism of PHF-tau purified from AD brain was investigated by microinjecting it into identified central neurons of the lamprey, a lower vertebrate. Dephosphorylation of 2 critical epitopes (the PHF-1 and TAU-1 sites), occurred within a few hours of PHF-tau microinjection, while proteolysis was complete by 2 days. These results constitute the first demonstration of the intracellular degradation of PHF-tau in an experimental in vivo system and suggest that the degradation of PHF-tau in situ is preceded by dephosphorylation. They also suggest that intracellular PHF-tau accumulation is primarily due to the failure of normal dephosphorylation and/or proteolytic mechanisms during neurofibrillary degenerative disease.

Hampel, H., S. J. Teipel, et al. (1999). "Discriminant power of combined cerebrospinal fluid tau protein and of the soluble interleukin-6 receptor complex in the diagnosis of Alzheimer's disease." Brain Res 823(1-2): 104-12.
Alzheimer's disease (AD) still can only be definitively diagnosed with certainty by examination of brain tissue. There is a great need for a noninvasive, sensitive and specific in vivo test for AD. We combined cerebrospinal fluid analyses of tau protein (levels were significantly increased in AD patients [p=0.0001]), a putative marker of neuronal degeneration, with components of the soluble interleukin-6 receptor complex (sIL-6RC: IL-6, soluble IL-6 receptor and soluble gp130), putative markers of neuroregulatory and inflammatory processes in the brain. A stepwise multivariate discriminant analysis revealed that tau protein and soluble gp130 (levels were significantly reduced in AD subjects [p=0.007]), the affinity converting and signal-transducing receptor of neuropoietic cytokines, maximized separation between the investigated groups. The discriminant function predicted 23 of 25 clinically diagnosed AD patients (sensitivity 92%) with mild to moderate dementia correctly as having AD. Furthermore, 17 of 19 physically and cognitively healthy age-matched control subjects (specificity 90%) were accurately distinguished by this test. Later predicting with the jackknife procedure each case in turn through the remaining patient group, the discriminant function remained stable. Our data suggest that multivariate discriminant analysis of combined CSF tau protein and sIL-6RC components may add more certainty to the diagnosis of AD, however, the method will need to be extended to an independent group of patients, comparisons and control subjects to assess the true applicability.

Hardy, J. and K. Gwinn-Hardy (1999). "Neurodegenerative disease: a different view of diagnosis." Mol Med Today 5(12): 514-7.
Neurodegenerative diseases have traditionally been defined as clinicopathological entities. Although this has been a productive paradigm in terms of the development of treatment strategies, molecular genetic approaches have revealed that there is overlap between different entities in pathogenic mechanisms. In this article, it is argued that neurodegenerative disease should also be thought of as the consequences of sequential biochemical processes, and that some parts of these processes appear to operate in more than one disease entity. Defining these pathways and, in particular, developing an appreciation of the commonalities between different diseases, should aid in the development of therapies that are effective in several diseases.

Hardy, J. (1999). "The shorter amyloid cascade hypothesis." Neurobiol Aging 20(1): 85; discussion 87.

Hattori, N., S. Sumino, et al. (1999). "[An 80-year-old woman with parkinsonism and progressive dementia]." No To Shinkei 51(6): 541-50.
We report an 80-year-old Japanese woman who presented levodopa-responsible parkinsonism followed by progressive dementia. She was well until her 61 years of age (in 1978) when she noted onset of resting tremor in her right hand followed by tremor in her right leg. She was treated with levodopa and trihexyphenidyl with good response, however, later on, she suffered from gait disturbance. In 1985, she had an episode of cardio-pulmonary arrest from which she was resuscitated, however, she started to show hypermetamorphosis, memory defect, and aggressive behaviors. She also developed motor fluctuations and dyskinesias from levodopa. She was admitted to our service in 1986; she showed rather typical parkinsonism and mild dementia. She received left Vim thalamotomy in the same year. Her dyskinesias improved, however, her gait disturbance became progressively worse. In 1995, she was admitted to our service again; she showed marked dementia and advanced parkinsonism; she was unable to walk unsupported. She became bedridden in 1996 and gastrostomy was placed. She was transferred to Zushi Aoki Hospital. Her dementia became progressively worse, and she was in the akinetic and mute state. She expired on April 22, 1998. She was discussed in a neurological CPC. The chief discussant arrived at a conclusion that the patient had Parkinson's disease with complication by Alzheimer's disease in her later clinical course. The diagnoses of participants were divided among Parkinson's disease with dementia, Parkinson's disease and Alzheimer's disease, and diffuse Lewy body disease. Postmortem examination revealed marked neuronal loss in the substantia nigra and the locus coeruleus. Lewy bodies were found in the substantia nigra. In addition, rather many Lewy bodies of cortical type were seen in the cingulate gylus, inferior temporal gylus, and in the amygdaloid nucleus. These Lewy bodies were positive for alpha-synuclein. Also, tau-positive intra-neuronal tangles were seen in the hippocampus and in the substantia nigra. The Meynert nucleus showed marked neuronal loss. Pathologic findings were consistent with the diagnosis of diffuse Lewy body disease.

Hensley, K., R. A. Floyd, et al. (1999). "p38 kinase is activated in the Alzheimer's disease brain." J Neurochem 72(5): 2053-8.
The p38 mitogen-activated protein kinase is a stress-activated enzyme responsible for transducing inflammatory signals and initiating apoptosis. In the Alzheimer's disease (AD) brain, increased levels of phosphorylated (active) p38 were detected relative to age-matched normal brain. Intense phospho-p38 immunoreactivity was associated with neuritic plaques, neuropil threads, and neurofibrillary tangle-bearing neurons. The antibody against phosphorylated p38 recognized many of the same structures as an antibody against aberrantly phosphorylated, paired helical filament (PHF) tau, although PHF-positive tau did not cross-react with the phospho-p38 antibody. These findings suggest a neuroinflammatory mechanism in the AD brain, in which aberrant protein phosphorylation affects signal transduction elements, including the p38 kinase cascade, as well as cytoskeletal components.

Herrmann, M., S. Golombowski, et al. (1999). "ELISA-quantitation of phosphorylated tau protein in the Alzheimer's disease brain." Eur Neurol 42(4): 205-10.
A reliable, sensitive and specific sandwich ELISA for the quantitation of paired helical filament (PHF) tau in human brain was developed using well-defined monoclonal antibodies. We examined rapid-autopsy-derived brain tissue from 21 neuropathologically confirmed Alzheimer's disease (AD) patients and 14 nondemented controls, matched for age, sex and postmortem delay times. We demonstrated significant elevations of phosphorylated tau levels in the frontal and parietal cortex as well as in the hippocampus of AD patients as compared to the nondemented controls. No difference was observed in the cerebellum. Phosphorylated tau levels measured by ELISA were significantly correlated with the presence or absence of neurofibrillary tangles.

Hoffmann, R., D. J. Craik, et al. (1999). "High level of aspartic acid-bond isomerization during the synthesis of an N-linked tau glycopeptide." J Pept Sci 5(10): 442-56.
An increased degree of utilization of the potential N-glycosylation site in the fourth repeat unit of the human tau protein may be involved in the inability of tau to bind to the corresponding tubulin sequence(s) and in the subsequent development of the paired helical filaments of Alzheimer's disease. To model these processes, we synthesized the octadecapeptide spanning this region without sugar, and with the addition of an N-acetyl-glucosamine moiety. The carbohydrate-protected, glycosylated asparagine was incorporated as a building block during conventional Fmoc-solid phase peptide synthesis. While the crude non-glycosylated analog was obtained as a single peptide, two peptides with the identical, expected masses, in approximately equal amounts, were detected after the cleavage of the peracetylated glycopeptide. Surprisingly, the two glycopeptides switched positions on the reversed-phase high performance liquid chromatogram after removal of the sugar-protecting acetyl groups. Nuclear magnetic resonance spectroscopy and peptide sequencing identified the more hydrophobic deprotected peak as the target peptide, and the more hydrophilic deprotected peak as a peptide analog in which the aspartic acid-bond just preceding the glycosylated asparagine residue was isomerized resulting in the formation of a beta-peptide. The anomalous chromatographic behavior of the acetylated beta-isomer could be explained on the basis of the generation of an extended hydrophobic surface which is not present in any of the other three glycopeptide variants. Repetition of the syntheses, with altered conditions and reagents, revealed reproducibly high levels of aspartic acid-bond isomerization of the glycopeptide as well as lack of isomerization for the non-glycosylated parent analog. If similar increased aspartic acid-bond isomerization occurs in vivo, a protein modification well known to take place for both the amyloid deposits and the neurofibrillary tangles in Alzheimer's disease, this process may explain the aggregation of glycosylated tau into the paired helical filaments in the affected brains.

Holzer, M., H. P. Holzapfel, et al. (1999). "Alterations in content and phosphorylation state of cytoskeletal proteins in the sciatic nerve during ageing and in Alzheimer's disease." J Neural Transm 106(7-8): 743-55.
Paired helical filaments containing the microtubule-associated protein tau in an abnormally high phosphorylated state are one of the major hallmarks of Alzheimer's disease. In the central nervous system, this neurofibrillar degeneration preferentially affects long-axon projection neurons. In the peripheral nervous system largely made up by long-axon neurons, formation of paired helical filaments, however, has only rarely been described. In the present study, we have analysed alterations in the content and phosphorylation state of tau and neurofilament protein in the sciatic nerve during ageing and in Alzheimer's disease. The amount of both cytoskeletal proteins remained constant during ageing but was significantly reduced in Alzheimer's disease. The phosphorylation state of tau protein was elevated during ageing as well as in Alzheimer's disease. No indications of a paired helical filament-like aggregation of tau were found. It is concluded that during normal ageing and in Alzheimer's disease, processes are activated in the peripheral nervous system that induce a hyperphosphorylation of tau. Increased phosphorylation of tau in peripheral neurons, however, is not necessarily accompanied by the formation of paired helical filaments. Analysing principal differences in the expression, posttranslational modification and metabolism of tau between central and peripheral neurons might, therefore, help to get a better insight into the mechanism of paired helical filament formation.

Horoupian, D. S. and P. H. Wasserstein (1999). "Alzheimer's disease pathology in motor cortex in dementia with Lewy bodies clinically mimicking corticobasal degeneration." Acta Neuropathol (Berl) 98(3): 317-22.
We report here a 70-year-old woman whose initial clinical presentation suggested corticobasal degeneration, but autopsy revealed dementia with Lewy bodies (DLB) with severe Alzheimer's disease (AD)-type pathology accentuated in the motor cortex, in conjunction with a high burden of both cortical and brain stem LB. Review of the literature disclosed four patients with AD whose peri-Rolandic region was particularly involved by the disease and who exhibited similar clinical and neuropathological findings as in our patient except they lacked LB. It appears that DLB if associated with severe AD-type pathology can, like some unusual cases of AD, mimic corticobasal degeneration.

Houlden, H., P. Rizzu, et al. (1999). "Apolipoprotein E genotype does not affect the age of onset of dementia in families with defined tau mutations." Neurosci Lett 260(3): 193-5.
We have assessed whether apolipoprotein E (ApoE) genotype influences the age of onset of dementia in a series of families with frontal temporal dementia with defined mutations in the tau gene. In contrast to the situation in Alzheimer's disease (AD), we could find no evidence that the age of onset of disease was influenced by the ApoE genotype.

Hugon, J., F. Esclaire, et al. (1999). "Toxic neuronal apoptosis and modifications of tau and APP gene and protein expressions." Drug Metab Rev 31(3): 635-47.
The causes and the mechanisms of neuronal death in Alzheimer's disease are not elucidated, although some new insights have been proposed over the past years, including free-radical toxicity, beta-amyloid toxicity, excitotoxicity, and disturbed cellular calcium metabolism. Some authors have also pointed out that apoptosis could play a role in neuronal degeneration, but it is still largely debated. Here, we review some recent data linking the induction of experimental neuronal apoptosis in vitro and the molecular pathology of the tau protein and amyloid precursor protein (APP). In cultures exposed to mild glutamate toxicity, tau mRNA expression, not beta-actin, is enhanced in stressed neurons. The Guam cycad toxin metabolite methylazoxymethanol also produces an increase of tau gene transcription that exacerbates changes induced by glutamate. In serum-deprived cultures or glutamate-exposed cultures, neurons committed to apoptosis have a reduced tau gene expression, whereas resistant neurons display a stable or even augmented tau mRNA expression accompanied by a persistent tau phosphorylation near serine 202. In the same conditions, stressed neurons produce membrane blebbings strongly immunopositive for APP and putative amyloidogenic fragments that are subsequently released in the extracellular space. Experimental apoptosis in neurons can recapitulate tau and APP modifications that could be associated with a selective vulnerability and a progression of cellular degeneration along the neuronal network.

Hull, M., J. Eistetter, et al. (1999). "Glutamate but not interleukin-6 influences the phosphorylation of tau in primary rat hippocampal neurons." Neurosci Lett 261(1-2): 33-6.
Alzheimer's disease (AD) is characterized by amyloid plaques, neuritic degenerations, disturbed glutamatergic neurotransmission and a peculiar inflammatory response. Diffuse plaques develop into neuritic plaques when neurites undergo degeneration in the plaque area. Hyperphosphorylation of tau proteins is a major step in neuritic pathology. Interleukin-6 (IL-6) has been found in diffuse and neuritic amyloid plaques in AD. Therefore the question arises whether IL-6 is involved in the transformation of diffuse into neuritic plaques by affecting tau phosphorylation. We investigated the influence of glutamate and IL-6 on tau phosphorylation in cultured primary rat hippocampal neurons. Glutamate but not IL-6 induced a dephosphorylation of tau. Furthermore IL-6 did not influence the glutamate-induced dephoshorylation of tau. We conclude that the role of IL-6 in AD is not related to the phosphorylation of tau.

Hulstaert, F., K. Blennow, et al. (1999). "Improved discrimination of AD patients using beta-amyloid(1-42) and tau levels in CSF." Neurology 52(8): 1555-62.
OBJECTIVE: To evaluate CSF levels of beta-amyloid(1-42) (Abeta42) alone and in combination with CSF tau for distinguishing AD from other conditions. METHODS: At 10 centers in Europe and the United States, 150 CSF samples from AD patients were analyzed and compared with 100 CSF samples from healthy volunteers or patients with disorders not associated with pathologic conditions of the brain (CON), 84 patients with other neurologic disorders (ND), and 79 patients with non-Alzheimer types of dementia (NAD). Sandwich ELISA techniques were used on site for measuring Abeta42 and tau. RESULTS: Median levels of Abeta42 in CSF were significantly lower in AD (487 pg/mL) than in CON (849 pg/mL; p = 0.001), ND (643 pg/mL; p = 0.001), and NAD (603 pg/mL; p = 0.001). Discrimination of AD from CON and ND was significantly improved by the combined assessment of Abeta42 and tau. At 85% sensitivity, specificity of the combined test was 86% (95% CI: 81% to 91%) compared with 55% (95% CI: 47% to 62%) for Abeta42 alone and 65% (95% CI: 58% to 72%) for tau. The combined test at 85% sensitivity was 58% (95% CI: 47% to 69%) specific for NAD. The APOE e4 gene load was negatively correlated with Abeta42 levels not only in AD but also in NAD. CONCLUSIONS: The combined measure of CSF Abeta42 and tau meets the requirements for clinical use in discriminating AD from normal aging and specific neurologic disorders.

Ingelson, M., M. Blomberg, et al. (1999). "Tau immunoreactivity detected in human plasma, but no obvious increase in dementia." Dement Geriatr Cogn Disord 10(6): 442-5.
Tau proteins are central to the neuropathology of Alzheimer's disease and tau levels in cerebrospinal fluid are elevated in affected individuals. In this study, we investigated the presence of tau in plasma from subjects with Alzheimer's disease (n = 16), frontotemporal dementia (n = 10), vascular dementia (n = 16) and from healthy controls (n = 15). By using an ELISA with monoclonal tau antibodies, tau immunoreactivity was detected in approximately 20% of the subjects. However, no difference between the disease and control groups was seen. After gel filtration of tau immunopositive plasma, the peak reactivity was found in the 160-kD fraction, indicating the source to be tau-like molecules of high-molecular-weight or polymers of low-molecular-weight tau isoforms. We conclude that measurements of tau in plasma cannot be utilized diagnostically for Alzheimer's disease or for the other dementias investigated. Copyrightz1999S.KargerAG,Basel

Ishiguro, K., H. Ohno, et al. (1999). "Phosphorylated tau in human cerebrospinal fluid is a diagnostic marker for Alzheimer's disease." Neurosci Lett 270(2): 91-4.
Microtubule-associated protein tau in cerebrospinal fluid (CSF) has been proposed as a diagnostic marker for Alzheimer's disease (AD), but there is overlap between AD patients and non-AD controls. To improve the diagnostic accuracy, we measured phosphorylated tau in CSF, because phosphorylated tau accumulates as pathological paired helical filaments in neurons of the AD brain. Immunoblot showed that CSF contained a 32 kDa N-terminal fragment of tau that was partially phosphorylated on Ser199, Thr231 and Ser235. A sandwich enzyme immunoassay revealed that phosphorylated CSF-tau levels were significantly higher in AD patients than those in non-AD controls. Discrimination between the two groups was clearer in phosphorylated CSF-tau than in total CSF-tau. The data indicate that elevated phosphorylated CSF-tau level is a more specific diagnostic marker for AD.

Ishihara, T., M. Hong, et al. (1999). "Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform." Neuron 24(3): 751-62.
Filamentous tau aggregates are hallmarks of tauopathies, e.g., frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC). Since FTDP-17 tau gene mutations alter levels/functions of tau, we overexpressed the smallest human tau isoform in the CNS of transgenic (Tg) mice to model tauopathies. These mice acquired age-dependent CNS pathology similarto FTDP-17 and ALS/PDC, including insoluble, hyperphosphorylated tau and argyrophilic intraneuronal inclusions formed by tau-immunoreactive filaments. Inclusions were present in cortical and brainstem neurons but were most abundant in spinal cord neurons, where they were associated with axon degeneration, diminished microtubules (MTs), and reduced axonal transport in ventral roots, as well as spinal cord gliosis and motor weakness. These Tg mice recapitulate key features of tauopathies and provide models for elucidating mechanisms underlying diverse tauopathies, including Alzheimer's disease (AD).

Janke, C., M. Beck, et al. (1999). "Phylogenetic diversity of the expression of the microtubule-associated protein tau: implications for neurodegenerative disorders." Brain Res Mol Brain Res 68(1-2): 119-28.
The microtubule-associated protein tau regulates the dynamic stability of the neuronal cytoskeleton by interacting with microtubules. It is encoded by a single gene, but expressed in a variety of isoforms due to differential RNA splicing. Six isoforms can be found in the human central nervous system. These isoforms differ in their ability to promote the assembly of microtubules as well as in their capacity to stabilize existing microtubule structures. Furthermore, some of the isoforms of tau are specifically involved in the pathogenesis of neurodegenerative disorders. Thus, splicing of tau might critically influence the physiological functions of tau protein as well as the pathogenesis of neurodegenerative diseases with tauopathy. The present study addresses the differential expression of the six isoforms of tau in the central nervous system of 12 mammalian species including Homo sapiens. The occurrence of each of the six tau isoforms was highly variable. However, species that were phylogenetically related expressed a similar pattern of tau isoforms. These results suggest a phylogenetic descent of splicing paradigms, which can be matched with known phylogenetic concepts based on morphological and molecular genetical studies. Especially, the unique expression pattern of tau isoforms in the human central nervous system implicates a possible link to the particular vulnerability of humans to neurodegenerative disorders with tauopathy, namely Alzheimer's disease, frontotemporal dementia and Pick's disease.

Jicha, G. A., C. Weaver, et al. (1999). "cAMP-dependent protein kinase phosphorylations on tau in Alzheimer's disease." J Neurosci 19(17): 7486-94.
To elucidate the role cAMP-dependent protein kinase (PKA) phosphorylations on tau play in Alzheimer's disease, we have generated highly specific monoclonal antibodies, CP-3 and PG-5, which recognize the PKA-dependent phosphorylations of ser214 and ser409 in tau respectively. The present study demonstrates by immunohistochemical analysis, CP-3 and PG-5 immunoreactivity with neurofibrillary pathology in both early and advanced Alzheimer's disease, but not in normal brain tissue and demonstrates that cAMP-dependent protein kinase phosphorylations on tau precede or are coincident with the initial appearance of filamentous aggregates of tau. Studies using heat-stable preparations demonstrate that neither site appears to be phosphorylated to any appreciable extent in normal rodent or human brain. Further analysis demonstrates that the beta catalytic subunit of PKA (Cbeta), the beta II regulatory subunit of PKA (RIIbeta), and the 79 kDa A-kinase-anchoring-protein (AKAP79), are tightly associated with the neurofibr