Neurofibrillary Tangles: 1998

NFT: 1998

Zhang, W., S. W. Han, et al. (1998). "Interaction of presenilins with the filamin family of actin-binding proteins." J Neurosci 18(3): 914-22.
Mutations in presenilin genes PS1 and PS2 account for approximately 50% of early-onset familial Alzheimer's disease (FAD). The PS1 and PS2 genes encode highly homologous transmembrane proteins related to the Caenorhabditis elegans sel-12 and spe-4 gene products. A hydrophilic loop region facing the cytoplasmic compartment is likely to be functionally important because at least 14 mutations in FAD patients have been identified in this region. We report here that the loop regions of PS1 and PS2 interact with nonmuscle filamin (actin-binding protein 280, ABP280) and a structurally related protein (filamin homolog 1, Fh1). Overexpression of PS1 appears to modify the distribution of ABP280 and Fh1 proteins in cultured cells. A monoclonal antibody recognizing ABP280 and Fh1 binds to blood vessels, astrocytes, neurofibrillary tangles, neuropil threads, and dystrophic neurites in the AD brain. Detection of ABP280/Fh1 proteins in these structures suggests that these presenilin-interacting proteins may be involved in the development of AD and that interactions between presenilins and ABP280/Fh1 may be functionally significant. The ABP280 gene is located on the human X chromosome, whereas the newly identified Fh1 gene maps to human chromosome 3. These results provide a new basis for understanding the function of presenilin proteins and further implicate cytoskeletal elements in AD pathogenesis.

Zambenedetti, P., R. Giordano, et al. (1998). "Metallothioneins are highly expressed in astrocytes and microcapillaries in Alzheimer's disease." J Chem Neuroanat 15(1): 21-6.
One of the neuropathological characteristics of Alzheimer's disease is the presence of a large number of reactive astrocytes, often, but not always, associated with senile plaques. The factors responsible for such an activation are as yet totally unknown. Other characteristic features of this disease such as betaA4 amyloid accumulation, senile plaques and neurofibrillary tangles represent well known pathological phenomena. Some studies suggest that betaA4 plays a major role in the reactive astrocytosis characteristic of Alzheimer's disease. In the normal human brain, metallothionein isoforms I and II are expressed in astrocytes but not in neurons. In the present study, we used anti-metallothionein antibodies to detect cells expressing metallothioneins isoforms I and II in normal and Alzheimer's disease (AD) brain sections. Results showed that expression of these proteins in the cortex, cerebral white matter and cerebellum is a relevant anatomopathological characteristic of Alzheimer's disease. Analysis of Alzheimer's disease brain sections revealed high expression of metallothioneins I/II in astrocytes and microcapillaries, and in the granular but not the molecular layer of the cerebellum. Furthermore, metallothionein expression can be used as a marker to identify subtypes of astrocytes.

Yoshida, H., A. Watanabe, et al. (1998). "Collapsin response mediator protein-2 is associated with neurofibrillary tangles in Alzheimer's disease." J Biol Chem 273(16): 9761-8.
Intraneuronal accumulation of paired helical filaments (PHF) is considered to be closely related to the neuronal loss observed in brains of patients affected with Alzheimer's disease. The central issue is whether PHF formation itself causes or accelerates the neuronal perikaryal and neuritic degeneration or whether they are simply the consequence of preceding degeneration. We sought to address the issue in part by characterizing the PHF-associated molecules and thus raised a number of monoclonal antibodies to neurofibrillary tangles. One monoclonal antibody, 3F4, strongly reacted with neurofibrillary tangles and some plaque neurites but few neuropil threads. This monoclonal antibody labeled a 65-kDa protein, but not tau or ubiquitin, on a Western blot of human brain extract and immunoprecipitated the same protein. The peptides released from the purified 65-kDa protein had the same sequences as those of a newly identified protein, human collapsin response mediator protein-2. Incorporation into neurofibrillary tangles may deplete soluble, cytosolic human collapsin response mediator protein-2 and lead to abnormal neuritic and/or axonal outgrowth of the tangle-bearing neuron, thus accelerating the neuritic degeneration in Alzheimer's disease.

Yilmazer-Hanke, D. M. (1998). "Alzheimer's disease. The density of amygdalar neuritic plaques is associated with the severity of neurofibrillary pathology and the degree of beta-amyloid protein deposition in the cerebral cortex." Acta Anat (Basel) 162(1): 46-55.
The gradual development of Alzheimer-related neurofibrillary changes and beta-amyloid deposits have been investigated in the amygdala and cerebral cortex with advanced silver methods. Neurofibrillary tangles occur within the somata of nerve cells, while neuropil threads are located in nerve cell processes. In neuritic plaques, there are both neuronal processes containing neurofibrillary changes and extracellular deposits of beta-amyloid protein. The amygdala early displays Alzheimer-type pathology and is typically rich in neuritic plaques. Neuritic plaques do not occur in the amygdala in the absence of neuropil threads and neurofibrillary tangles in the entorhinal region and amygdala. In contrast to the gradual increase in the number of neurofibrillary tangles and neuropil threads, neuritic plaques grow in size and number along with advancement in the neurofibrillary and beta-amyloid pathology. The findings indicate that neuropil threads and neurofibrillary tangles in the entorhinal region and amygdala precede neuritic plaques in the amygdala, and the density of neuritic plaques is related both to the degree of neurofibrillary and beta-amyloid pathology in the cerebral cortex.

Yao, P. J. and P. D. Coleman (1998). "Reduction of O-linked N-acetylglucosamine-modified assembly protein-3 in Alzheimer's disease." J Neurosci 18(7): 2399-411.
Abnormal protein processing and modification is associated with Alzheimer's disease (AD) pathology. The role of phosphorylation in AD has been studied extensively because the presumed abnormal phosphorylation of tau protein is believed to play a role in the formation of paired helical filaments. Glycosylation with O-linked N-acetylglucosamine (O-GlcNAc) to serine and threonine residues is a dynamic protein modification of intracellular proteins, and it shares similar features with protein phosphorylation. In this study, O-GlcNAc glycosylation of proteins from autopsied human brains with confirmed AD and non-AD age-matched controls was examined. O-GlcNAcylation was demonstrated by labeling protein extracts with [3H]galactose in the presence of galactosyltransferase and subsequent analyses of saccharide-protein linkage and saccharide structure. The number of O-GlcNAc-containing proteins and the overall O-GlcNAc level do not appear to be different between AD and control brain tissues. The only significant change observed is a marked reduction of O-GlcNAcylated clathrin assembly protein-3 (AP-3) in AD. The reduction is more evident in brain neocortical regions, and there appears to be a negative correlation between O-glycosylated AP-3 and the density of neurofibrillary tangles. These data suggest a possible association between the O-glycosylated AP-3 and AD pathology.

Yao, P. J. and P. D. Coleman (1998). "Reduced O-glycosylated clathrin assembly protein AP180: implication for synaptic vesicle recycling dysfunction in Alzheimer's disease." Neurosci Lett 252(1): 33-6.
Synapse loss is one of the neuropathologies in Alzheimer's disease (AD) that may play a crucial role in the mechanism of its distinct cognitive impairment and dementia. In a previous study [18], a significant reduction of O-glycosylated clathrin assembly protein AP180 was observed in neocortex of AD. The reduction correlated with the density of neurofibrillary tangles. In this study we further determine that the O-GlcNAc/AP180 ratio is not changed, but the level of AP180 protein decreases in AD. Furthermore, whereas the level of neurofilament (NF-M) remains relatively unchanged, another clathrin assembly protein, AP-2, is also reduced in AD along with a small loss of synaptophysin. Our findings suggest that synaptic vesicle recycling dysfunction may be involved in the pathology of synapse loss in AD.

Yankner, B. A. (1998). "Monster plaques: what they tell us about Alzheimer's disease." Nat Med 4(4): 394-5.

Yang, A. J., D. Chandswangbhuvana, et al. (1998). "Loss of endosomal/lysosomal membrane impermeability is an early event in amyloid Abeta1-42 pathogenesis." J Neurosci Res 52(6): 691-8.
Previous studies have implicated the failure to degrade aggregated Abeta1-42 in late endosomes or secondary lysosomes as a mechanism for the accumulation of beta-amyloid in Alzheimer's disease. We examined the consequences of intracellular accumulation of Abeta1-42 on the integrity of the endosomal/lysosomal compartment by monitoring Lucifer Yellow fluorescence and the release of lysosomal hydrolases into the soluble, cytosolic fraction. In control cells, the Lucifer Yellow fluorescence is observed as punctate staining in a perinuclear distribution with no apparent cytoplasmic fluorescence, consistent with its localization in late endosomes or secondary lysosomes. After incubation with Abeta1-42 for 6 hr, a loss of lysosomal membrane impermeability is observed as evidenced by redistribution of the fluorescence to a diffuse, cytoplasmic pattern. The loss of lysosomal membrane impermeability is correlated with Abeta1-42 accumulation, since incubation of the cells with the nonaccumulating isoform of amyloid, Abeta1-40, does not induce leakage. The same results were obtained using the release of soluble lysosomal hydrolases, cathepsin D and beta-hexosaminidase, into the cytosol as an assay for the leakage of lysosomal contents. Together, our results suggest that the loss of lysosomal membrane impermeability may be an early event in Abeta pathogenesis, and provide an explanation for the miscompartmentalization of extracellular and cytoplasmic components observed in Alzheimer's disease (AD). The release of hydrolases may further cause the breakdown of the cytoskeleton and the blebbing of the plasma membrane, and the leakage of heparan sulfate glycosaminoglycans from the lysosome may ultimately promote the assembly of tau into neurofibrillary tangles (NFT).

Yamada, T., Y. Yoshiyama, et al. (1998). "Possible roles of transglutaminases in Alzheimer's disease." Dement Geriatr Cogn Disord 9(2): 103-10.
The localizations of two transglutaminases [factor XIIIa and tissue transglutaminase (tTG)] and their mRNAs were examined in human brain tissues from neurologically normal and Alzheimer disease (AD) cases, using immunohistochemical and in situ hybridization methods. In all cases, meningeal macrophages and ependymal macrophage/microglia were positive for factor XIIIa. The mRNA encoding factor XIIIa was detected in macrophages and microglia. As reported previously, intense staining with the antibody to factor XIIIa of a subset of microglia was seen in the parietal cortex in AD brains. Few or no microglia were found associated with classical senile plaques. In contrast, many labeled microglia were associated with primitive plaques. Further-more, most of these cells were mainly seen in the subpial cortical layer but were very rare in the hippocampus. On the other hand, few factor-XIIIa-positive microglia were found in the parietal cortices from non-neurological cases, but moderate numbers were found in their hippocampal tissues. TG and its mRNA were localized in astrocytes in all the cases. In AD, a few neurofibrillary tangles were positive to tTG. These results suggest that the subsets of microglia which express factor XIIIa may play some roles in the early phase of AD pathology.

Xia, M. Q., O. Berezovska, et al. (1998). "Lack of specific association of presenilin 1 (PS-1) protein with plaques and tangles in Alzheimer's disease." J Neurol Sci 158(1): 15-23.
Missense mutations in the presenilin-1 (PS-1) gene are causally related to the majority of familial early-onset Alzheimer's disease (FAD). PS-1 immunohistochemical expression in normal human brain and in brains with Alzheimer's disease (AD) has so far been controversial. Here, we report a study of PS-1 expression in brains, cell lines and peripheral blood mononuclear cells using a panel of well characterized PS-1-specific antibodies. These antibodies were characterized by immunofluorescent staining of PS-1 transfectants followed by flow cytometric analysis. In human brain, widespread neuronal staining was observed. PS-1 immunoreactivity was primarily confined to neuronal cell bodies and proximal dendrites. Weaker staining of microglia was also detected, in accord with the finding of PS-1 immunoreactivity in monocytes. PS-1 expression is not particularly associated with neurons either containing or spared from neurofibrillary tangles, nor with senile plaques. The level of PS-1 expression does not differ between normal and AD brains. Immunoprecipitation from AD, FAD and control brains revealed only a 32 kDa N-terminal fragment and an 18-20 kDa C-terminal fragment. Little or no full length PS-1 was detected. The enriched presence of PS-1 in neurons implies an important role in neuronal function, however, the lack of apparent association of its expression with AD pathology signifies the need for a better understanding of its pathophysiological role.

Williams, K. R., A. M. Saunders, et al. (1998). "Uptake and internalization of exogenous apolipoprotein E3 by cultured human central nervous system neurons." Neurobiol Dis 5(4): 271-9.
Apolipoprotein E (apoE) has been confirmed as a risk factor for late-onset Alzheimer's disease (AD) and is associated with neurofibrillary tangles and senile plaques, the microscopic pathological characteristics of AD. There has been no direct evidence that human central nervous system neurons can take up and internalize exogenous apoE, which may be important in order for apoE to be involved in the development of the disease. This paper demonstrates by immunohistochemistry and confocal microscopy that cultured human brain neurons can take up and internalize exogenous recombinant human apoE3. We confirm that neurons express the low-density lipoprotein receptor-related protein (LRP) but do not express the low-density lipoprotein receptor. We also demonstrate that the LRP mediates the neuronal uptake of apoE.

Wickelgren, I. (1998). "Tracking insulin to the mind." Science 280(5363): 517-9.

Weber, K., W. Schmahl, et al. (1998). "Distribution of advanced glycation end products in the cerebellar neurons of dogs." Brain Res 791(1-2): 11-7.
Nonenzymatically glycated proteins and their advanced stage, the 'advanced glycation end products' (AGEs), have been detected in long-lived proteins and protein deposits in human and animal tissues. They are thought to be associated with normal aging and particularly with the pathogenesis of diabetic complications and Alzheimer's disease. AGEs accumulate in human neurons in an age-dependent manner and, in Alzheimer's disease patients, particularly in amyloid plaques and neurofibrillary tangles. In this study, we demonstrate AGE immunoreactivity in the canine brain, particularly in cerebellar Purkinje cells and brainstem neurons. In addition, distinct AGE-positive granules can be detected in the Purkinje cells which accumulate in an age-dependent manner. Staining with PAS and oil-red suggests that these AGE-positive granules contain the protein, but not the lipid constituents associated with lipofuscin. Our results show that the pattern of AGE distribution in the canine cerebellum resembles the situation in the human brain, but that the time course of AGE formation is much faster in dogs reflecting their much shorter life span.

Warzok, R. W., C. Kessler, et al. (1998). "Apolipoprotein E4 promotes incipient Alzheimer pathology in the elderly." Alzheimer Dis Assoc Disord 12(1): 33-9.
To evaluate the influence of the apolipoprotein E (ApoE) epsilon4 allele on the age at which Alzheimer-like lesions appear in the brain, we analyzed the degree of cerebral beta-amyloidosis and neurofibrillary tangle formation in the hippocampal formation and adjacent cortical areas 28, 27, and 36 of persons who had died between the ages of 50 and 93 years and who had shown no signs of clinical dementia. The occurrence of the three common polymorphisms of the ApoE gene in this sample of 147 routine autopsy cases from eastern Germany was comparable to previously reported values in European and North American populations: ApoEepsilon2/2, 0.7%; ApoEepsilon2/3, 14.3%; ApoEepsilon2/4, 4.1%; ApoEepsilon3/3, 56.5%; ApoEepsilon3/4, 22.4%; and ApoEepsilon4/4, 2.0%. Nondemented persons carrying the ApoEepsilon4 allele were significantly more likely to have senile plaques, diffuse amyloid deposits, cerebrovascular amyloid, and neurofibrillary tangles than were those lacking E4. Comparing the two largest ApoE subgroups, ApoEepsilon3/3 and ApoEepsilon3/4, the relative increase in the occurrence of beta-amyloid in the epsilon3/4 group was evident by the mid-60s, with the relative increase in neurofibrillary tangles in this group emerging slightly earlier. The ApoEepsilon2 allele appears to delay the appearance of the lesions somewhat. We conclude that ApoEepsilon4 promotes the early appearance of beta-amyloid and neurofibrillary tangles in the elderly and that the increased frequency of these lesions is related to the higher risk of Alzheimer disease in persons bearing the ApoEepsilon4 allele.

Walker, D. G. and P. L. McGeer (1998). "Vitronectin expression in Purkinje cells in the human cerebellum." Neurosci Lett 251(2): 109-12.
Vitronectin (Vn) is a multi-functional protein that has a role in cell adhesion, and regulation of complement and blood coagulation. It has been shown to colocalize with amyloid beta peptide containing plaques and neurofibrillary tangles in Alzheimer's (AD) disease. Its normal localization in human brain tissue has not been described. In this study, Vn immunoreactivity in Purkinje cells in the human cerebellar cortex is demonstrated. This staining was present in sections from both neurologically normal and disease-affected cases. Using reverse transcription-polymerase chain reaction procedures, Vn mRNA was detected in RNA extracted from human cerebellum and cortex, from human NT2-derived neurons and from undifferentiated and differentiated SH-SY5Y neuroblastoma cells.

Wakabayashi, K., A. Kakita, et al. (1998). "Apolipoprotein E epsilon4 allele and progression of cortical Lewy body pathology in Parkinson's disease." Acta Neuropathol (Berl) 95(5): 450-4.
To elucidate whether the apolipoprotein E epsilon4 allele (APOE4) affects cortical neuropathology in Parkinson's disease (PD), we determined APOE genotypes and quantified the densities of cortical Lewy bodies (LBs), amyloid plaques and neurofibrillary tangles in 22 autopsy-proven PD cases (12 with dementia; 10 without dementia) that were not accompanied by Alzheimer's disease. The APOE4 frequency in the demented patient group was 0.21, which was significantly higher than that in Japanese controls (P < 0.04). LB densities in demented PD patients were significantly higher than those in non-demented PD patients, despite the shorter disease duration in the former. Moreover, plaque density in the temporal cortex and LB density in the cingulate cortex were significantly higher in the group with APOE4 than in that without the allele. There was no difference in tangle density between these two groups. These results suggest that APOE4 may influence the increase in the number of cortical LBs and amyloid plaques in PD. It is possible that when PD occurs in individuals with APOE4, concomitantly evolving cortical LB pathology in a proportion of cases results in limbic (transitional) or neocortical-type LB disease.

Vogt, B. A., L. J. Vogt, et al. (1998). "Multivariate analysis of laminar patterns of neurodegeneration in posterior cingulate cortex in Alzheimer's disease." Exp Neurol 153(1): 8-22.
Posterior cingulate cortex is the site of earliest reductions in glucose metabolism and qualitatively different laminar patterns of neurodegeneration in Alzheimer's disease (AD). This study used multivariate analyses of area 23 in 72 cases of definite AD to assess relationships between laminar patterns of neurodegeneration, neurofibrillary tangle (NFT) and senile plaque (SP) densities, age of disease onset and duration, and apolipoprotein E (ApoE) genotype. No age-related changes in neurons occurred over four decades in 17 controls and regression analysis of all AD cases showed no relationships between neuron, SP, and tau-immunoreactive NFT densities. Principal components analysis of neurons in layers III-Va and eigenvector projections showed five subgroups. The subgroups were independent because each had a full range of disease durations and qualitatively different laminar patterns in degeneration suggested disease subtypes (ST). Cases with most severe neuron losses (STSevere) had an early onset, most SP, and highest proportion of ApoE epsilon4 homozygotes. Changes in the distribution of NFT were similar over disease course in two subtypes and NFT did not account for most neurodegeneration. In STII-V with moderate neuron loss in most layers, cases with no NFT had a disease duration of 3.5 +/- 0.9 years (mean +/- SEM), those with most in layers IIIc or Va had a duration of 7.3 +/- 1 years, and those with most in layers II-IIIab had a duration of 12.1 +/- 1 years. In STSevere, cases with highest NFT densities in layers II-IIIab also were late stage. Finally, epsilon4 homozygotes were most frequent in STSevere, but four statistical tests showed that this risk is not directly involved in neurodegeneration. In conclusion, multivariate pattern recognition shows that AD is composed of independent neuropathological subtypes and NFT in area 23 do not account for most neuron losses.

Vincent, I., J. H. Zheng, et al. (1998). "Mitotic phosphoepitopes precede paired helical filaments in Alzheimer's disease." Neurobiol Aging 19(4): 287-96.
We have shown previously that the TG-3 and MPM-2 antibodies recognize phosphoepitopes common to mitosis and degenerating neurons of Alzheimer's disease(AD) brain. Here, we have evaluated their occurrence in human brain biopsy tissue, and confirm that they are absent in mature neurons of adult brain, but reappear during neurodegeneration in AD. The TG-3 epitope appears ahead of the MPM-2 epitope and is distributed throughout the neuronal soma. Tau is the major TG-3 antigen in AD brain. The initial localization of MPM-2 immunoreactivity in primary dendrites, it's robust occurrence in granulovacuolar bodies, and the increased immunoreactivity with 300-350-kDa proteins, suggest MAPI B as a candidate MPM-2 antigen in AD. Production of mitotic phosphepitopes in more than one type of human neurodegenerative lesion implicates mitotic kinases as common mediators of neuronal death. Because mitotic phosphoepitopes appear before paired helical filaments, it is suggested that mitotic kinase activation triggers neurofibrillary tangle formation. Future studies will need to focus on factors influencing mitotic kinase activity, a point with potential for early diagnosis and disease abrogation.

Viitanen, M., K. Johansson, et al. (1998). "Alzheimer changes are common in aged drivers killed in single car crashes and at intersections." Forensic Sci Int 96(2-3): 115-27.
With increasing age, diseases affecting the cognitive functions are more frequent. These diseases may increase the risk for fatal car crashes. We analyzed the frequency of neuropathological alterations characteristic of Alzheimer's disease (i.e. neuritic and diffuse plaques, and neurofibrillary tangles) in two association areas of the brain, parietal and frontal cerebral cortex, from 98 fatally injured aged drivers. In the age groups of 65-75 and over 75 years of age, 50% and 72% of the drivers, respectively, had neuritic plaques in either parietal and/or frontal cortex. In 14% of all killed drivers the number of neuritic plaques reached the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) age-related histologic score C, which indicates the diagnosis of Alzheimer's disease (AD), and an additional 33% had score B, which suggests the diagnosis of AD. Neuropathological AD changes were most common in the brains of drivers killed in single vehicle crashes, followed by multivehicle crashes at intersections and least common in multivehicle crashes elsewhere, but the differences did not reach statistical significance. In a great majority (80-85%) of cases the killed aged driver was the guilty party of the crash. The results imply, that incipient AD may contribute to fatal crashes of aged drivers, and therefore the forensic autopsy of these victims should include neuropathological examination.

Velasco, M. E., M. A. Smith, et al. (1998). "Striation is the characteristic neuritic abnormality in Alzheimer disease." Brain Res 813(2): 329-33.
In this study, we found that neuropil threads of Alzheimer disease, rather than being continuous filaments along cell processes, show multiple interruptions. They are segmental in nature and therefore appear as striations rather than continuous filaments along the length of the neurite. Neuritic striation is not an artifact of section thickness since the majority of abnormal filament accumulations are extremely short. The dominance of short striations demonstrates that argyrophilic grains, rather than being distinct structures, simply represent a short variant of striation and that longer striations are arbitrarily considered neuropil threads. Ultrastructural examination showed that the intervals between striations lack a cytoskeleton. We suggest that neuritic striations may interrupt the microtubule system functionally blocking fast neuritic transport as well as playing a role in loss of neuronal connectivity.

van Leeuwen, F. W., D. P. de Kleijn, et al. (1998). "Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients." Science 279(5348): 242-7.
The cerebral cortex of Alzheimer's and Down syndrome patients is characterized by the presence of protein deposits in neurofibrillary tangles, neuritic plaques, and neuropil threads. These structures were shown to contain forms of beta amyloid precursor protein and ubiquitin-B that are aberrant (+1 proteins) in the carboxyl terminus. The +1 proteins were not found in young control patients, whereas the presence of ubiquitin-B+1 in elderly control patients may indicate early stages of neurodegeneration. The two species of +1 proteins displayed cellular colocalization, suggesting a common origin, operating at the transcriptional level or by posttranscriptional editing of RNA. This type of transcript mutation is likely an important factor in the widely occurring nonfamilial early- and late-onset forms of Alzheimer's disease.

Uchihara, T., H. Mizusawa, et al. (1998). "Discrepancy between tau immunoreactivity and argyrophilia by the Bodian method in neocortical neurons of corticobasal degeneration." Acta Neuropathol (Berl) 96(6): 553-7.
To clarify different features of cytoskeletal pathology in neocortical neurons between corticobasal degeneration (CBD) and Alzheimer's disease (AD), the relationship between neurofibrillary tangles (NFTs), which are defined as a fibrillary structure stained by the Bodian method, and tau-immunopositive neurons in layers II-III of the premotor cortex was assessed by sequential staining for tau immunohistochemistry followed by the Bodian method on the same section. In AD brains, tau-like immunoreactivity in neurons was uniformly colocalized with Bodian-positive NFTs. In CBD brains, however, tau-immunopositive neurons could be classified into three different types: (1) those not stained at all by the Bodian method (diffuse cytoplasmic type), which represented the majority of these immunopositive neurons, (2) some partly stained by the Bodian method (mixed type), and (3) a few for which argyrophilia demonstrated by the Bodian method was completely colocalized with immunoreactivity (NFT type). This discrepancy between tau-like immunoreactivity and Bodian method is characteristic of CBD and suggests that the tau molecule is less liable to form argyrophilic fibrils in neocortical neurons of CBD.

Tortosa, A., E. Lopez, et al. (1998). "Bcl-2 and Bax protein expression in Alzheimer's disease." Acta Neuropathol (Berl) 95(4): 407-12.
Beta-amyloid deposition and neurofibrillary degeneration are important pathological findings in the brains of patients with Alzheimer's disease (AD). In the present study, we have examined Bcl-2 and Bax immunoreactivity in the hippocampus of AD cases, with special attention to the possible relationship between Bcl-2 and Bax immunoreactivity, and neurofibrillary degeneration and senile plaques. Different antibodies were used, including Bcl-2 (N-19), Bcl-2 (BioGenex), Bax (P-19) and Bax (N-20), and their specificity was tested on Western blots of brain homogenates. No differences between Bcl-2 and Bax immunoreactivity in tangle-bearing and non-tangle-bearing neurons were observed, thus suggesting that Bcl-2 and Bax do not participate in tangle formation. Overexpression of Bcl-2 protein in reactive glial cells surrounding senile plaques suggests that Bcl-2 may play a role in the survival of reactive glia. On the other hand, overexpression of Bax immunoreactivity in dystrophic neurites of senile plaques suggests that Bax is associated with neurite degeneration in senile plaques. Finally, Bax (P-19), but not Bax (N-20), immunoreactivity was localized in amyloid fibrils of senile plaques. Since Western blots to Bax (P-19) recognize multiple bands in addition to the expected band of about 21 kDa, it is suggested that Bax (P-19) immunoreactivity of amyloid fibrils is not specific.

Torp, R., J. H. Su, et al. (1998). "GADD45 is induced in Alzheimer's disease, and protects against apoptosis in vitro." Neurobiol Dis 5(4): 245-52.
Expression of the growth arrest DNA damage-inducible protein, GADD45, has recently been reported to be induced by a wide range of stimuli, especially those that produce a high level of base pair damage. We have investigated the expression of GADD45 in brain tissue obtained from patients suffering from Alzheimer's disease (AD). Our results demonstrate that many neurons express the GADD45 protein, and that expression of this protein in neurons is associated with expression of the anti-apoptotic protein Bcl-2, and the presence of DNA damage, but not closely associated with tangle-bearing neurons. Additionally, cell lines overexpressing this protein confer resistance to apoptosis induced by DNA damage agent, suggesting that this protein may participate in cell survival mechanisms.

Toide, K., M. Shinoda, et al. (1998). "A novel prolyl endopeptidase inhibitor, JTP-4819--its behavioral and neurochemical properties for the treatment of Alzheimer's disease." Rev Neurosci 9(1): 17-29.
Formation of beta-amyloid and neurofibrillary tangles in the brain due to genetic or other factors is the most frequent cause of Alzheimer's disease. In addition, marked reduction of certain brain neuropeptide levels is a consistent finding in patients with Alzheimer's disease, together with the deterioration of cholinergic neurons. Currently, there is great demand for the development of new drugs to improve memory deficits or to delay the neurodegenerative process in conditions such as Alzheimer's disease. In this report, the pharmacological actions of JTP-4819, a novel specific prolyl endopeptidase (PEP) inhibitor devised for the treatment of Alzheimer's disease, are reviewed with respect to its effects on PEP activity, neuropeptidergic and cholinergic neurons, and memory-related behavior in rats. We also discuss the possible beneficial effect of JTP-4819 on beta-amyloid metabolism and its potential neuroprotective properties.

Thorns, V., L. Hansen, et al. (1998). "nNOS expressing neurons in the entorhinal cortex and hippocampus are affected in patients with Alzheimer's disease." Exp Neurol 150(1): 14-20.
Nitric oxide is a multifunctional molecule that acts as messenger/modulator in synaptogenesis and potential neurotoxin and is synthesized by three isozymes of Nitric oxide synthase (NOS). The role of NOS in Alzheimer's disease (AD) is unclear. For example, neurons in the entorhinal cortex (EC) that are highly vulnerable to neurodegeneration in AD express low levels of NOS and while it has been suggested that the inducible form of NOS is upregulated in AD, it is still not clear if the constitutive expressed isozyme (nNOS) is involved in the process of neurodegeneration. In order to better understand the role of nNOS in the pathogenesis of AD, sections from the EC and hippocampus (HC) of AD and control cases were immunohistochemically analyzed by single- and double-immunolabeling using antibodies against nNOS and PHF-tau. Semiquantitative assessment of numbers of nNOS expressing neurons in different areas of the HC and EC showed a remarkable loss of nNOS expressing neurons in the entorhinal cortex layer II and--less severe--CA1 and CA3 of the hippocampus in patients with AD. In addition, double-immunolabeling studies revealed that nNOS is strongly associated with neurofibrillary tangles and plaques. These findings indicate that nNOS expressing neurons are highly susceptible to neurodegeneration and that nNOS might contribute to the pathogenesis of AD.

Thal, D. R., W. Hartig, et al. (1998). "Stage-correlated distribution of type 1 and 2 dystrophic neurites in cortical and hippocampal plaques in Alzheimer's disease." J Hirnforsch 39(2): 175-81.
Two types of dystrophic neurites have been described in neuritic plaques in Alzheimer's disease (AD). Type 1 dystrophic neurites display tau-positive paired helical filaments (PHF) while those of type 2 are swollen and positive for both amyloid precursor protein and Chromogranin A. To determine the role of these two types of dystrophic neurites in the development of neuritic plaques, we examined their distribution in CA 1, CA 4, the entorhinal and the temporal cortex throughout all Braak-stages. Fourty cases with AD-related neurofibrillary changes were evaluated semi-quantitatively. The frequency of neuritic plaques displaying both types of dystrophic neurites seemed to increase from stage I to stage IV and to remain stable or slightly decrease in later stages. Staining combinations detecting type 1 (Gallyas, immunohistochemistry against hyperphosphorylated tau-protein) and type 2 dystrophic neurites simultaneously (immunohistochemistry against the amyloid precursor protein or Chromogranin A) showed coexpression of the type 1 and type 2 pattern in single neurites of neuritic plaques. In the entorhinal and temporal cortex, occasional neuritic plaques displayed tau-immunopositive changes in the absence of swollen type 2 neurites. Since amyloid precursor protein is expressed in distal ends of neurites after various brain lesions we suggest that amyloid precursor protein-positive neurites in neuritic plaques indicate dysfunctional axonal transport due to type 1 neurofibrillary changes.

Thal, D. R., T. Arendt, et al. (1998). "Progression of neurofibrillary changes and PHF-tau in end-stage Alzheimer's disease is different from plaque and cortical microglial pathology." Neurobiol Aging 19(6): 517-25.
In terminal Alzheimer's disease (AD) the frequency of plaques was found to be reduced in single cases. To test this finding in a larger sample, and in order to determine whether the number of plaques labeled with different markers and the distribution of neurofibrillary tangles are correlated positively to each other and to the degree of dementia, a sample of 134 autopsy brains with and 15 without AD-related pathology has been examined. All of the cases were staged according to Braak and Braak. Both the frequency of plaques immunopositive for beta-amyloid, amyloid precursor protein, and apolipoprotein E and that of microglial cells in the cortex and in the white matter were determined semiquantitatively. The content and distribution of PHF-tau was ascertained by ELISA and immunohistochemistry. Both the clinical dementia rating and the global deterioration scale were used as clinical parameters retrospectively. Correlation coefficients were calculated for all parameters and differences were evaluated statistically. With progressive distribution of neurofibrillary tangles and increasing content of PHF-tau the plaque stages and the degree of cortical microglia reaction increased up to the Braak-stages IV and V, thereafter showing a slightly decreasing tendency in the investigated regions. In end-stage AD resorption of beta-amyloid seems to surpass its deposition. The microglial reaction in the white matter correlated neither with the Braak-stage nor with the accumulation of amyloid. With regard to the degree of dementia, both scales correlated well with the pathological changes. Our data show that neuronal cytoskeletal alterations progressively increase with progressive dementia until the end stage of AD in contrast to the frequencies of plaques and cortical microglial cells, and are therefore preferable for staging purposes.

Takeda, A., M. Mallory, et al. (1998). "Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders." Am J Pathol 152(2): 367-72.
The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as a-synuclein) is a presynaptic terminal molecule that accumulates in the plaques of Alzheimer's disease. Recent studies have shown that a mutation in NACP is associated with familial Parkinson's disease, and that Lewy bodies are immunoreactive with antibodies against this molecule. To clarify the patterns of accumulation and differences in abnormal compartmentalization, we studied NACP immunoreactivity using double immunolabeling and laser scanning confocal microscopy in the cortex of patients with various neurodegenerative disorders. In Lewy body variant of Alzheimer's disease, diffuse Lewy body disease, and Parkinson's disease, NACP was found to immunolabel cortical Lewy bodies, abnormal neurites, and dystrophic neurites in the plaques. Double-labeling studies showed that all three of these neuropathological structures also contained ubiquitin, synaptophysin, and neurofilament (but not tau) immunoreactivity. In contrast, neurofibrillary tangles, neuropil threads, Pick bodies, ballooned neurons, and glial tangles (most of which were tau positive) were NACP negative. These results support the view that NACP specifically accumulates in diseases related to Lewy bodies such as Lewy body variant of Alzheimer's disease, diffuse Lewy body disease, and Parkinson's disease and suggests a role for this synaptic protein in the pathogenesis of neurodegeneration.

Takashima, A., T. Honda, et al. (1998). "Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25-35) enhances phosphorylation of tau in hippocampal neurons." Neurosci Res 31(4): 317-23.
According to the amyloid hypothesis for the pathogenesis of Alzheimer's disease (AD), amyloid beta peptide (Abeta) directly affects neurons, leading to neurodegeneration and tau phosphorylation, followed by the production of paired helical filaments (PHF) in neurofibrillary tangles (NFT). To analyze the relationship between the phosphorylation sites of tau and the activation of kinases in response to Abeta, we treated cultured rat hippocampal neurons with a peptide fragment of Abeta, Abeta(25-35). Abeta(25-35) treatment activated tau protein kinase I/glycogen synthase kinase-3beta (TPKI/GSK-3beta) but not glycogen synthase kinase-3alpha (GSK-3alpha) or mitogen activated protein kinase (MAP kinase) in primary culture of hippocampal neurons. Using antibodies that recognize phosphorylated sites of tau, we showed that tau phosphorylation was enhanced in at least five sites (Ser199, Ser202, Ser396, Ser404, and Ser413 numbered according to the human tau isoform containing 441 amino acid residues), to an extent that depended on the level of TPK I/GSK-3beta. Treatment with TPK I/GSK-3beta antisense oligonucleotide inhibited the enhancement of tau phosphorylation induced by Abeta(25-35) exposure. Thus, TPK I/GSK-3beta activation by Abeta(25-35) may lead to extensive tau phosphorylation.

Swaab, D. F., P. J. Lucassen, et al. (1998). "Reduced neuronal activity and reactivation in Alzheimer's disease." Prog Brain Res 117: 343-77.
1. Alzheimer's disease is a multifactorial disease in which age and APOE-epsilon 4 are important risk factors. Various mutations and even viral infections such as herpes simplex (Itzhaki et al., 1997) may play an additional role. 2. The neuropathological hallmarks of Alzheimer's disease (AD), i.e. amorphous plaques, neuritic plaques (NPs), pretangles, neurofibrillary tangles (NFT) and cell death are not part of a single pathogenetic cascade but are basically independent phenomena. 3. Pretangles can occur in neurons from which the metabolic rate is not altered. However, in brain areas where classical AD changes, i.e. NPs and NFTs, are present, such as the CA1 area of the hippocampus, the nucleus basalis of Meynert and the tuberomamillary nucleus, a decreased metabolic rate is found. Decreased metabolic rate appears to be an independent phenomenon in Alzheimer's disease. It is not induced by the presence of pretangles, NFT or NPs. 4. Decreased metabolic rate may precede cognitive impairment and is thus an early occurring hallmark of Alzheimer's disease, which, in principle, may be reversible. The observation that the administration of glucose or insulin enhances memory in Alzheimer patients also supports the view that Alzheimer's disease is basically a metabolic disease. Moreover, several observations indicate that activated neurons are better able to withstand aging and AD, a phenomenon paraphrased by us as "use it or lose it". It is, therefore, attractive to direct the development of therapeutic strategies towards restimulation of neuronal metabolic rate in order to improve cognition and other symptoms in Alzheimer's disease. A number of pharmacological and non-pharmacological studies support the concept that activation of the brain indeed has beneficial effects on several aspects of cognition and other central functions.

Stein, D. J., M. S. Buchsbaum, et al. (1998). "Greater metabolic rate decreases in hippocampal formation and proisocortex than in neocortex in Alzheimer's disease." Neuropsychobiology 37(1): 10-9.
Neuropathological studies of Alzheimer's disease (AD) have found pathological changes in some cytoarchitectural regions and relative sparing in others. Positron emission tomography (PET) studies have also shown selective decreases in glucose metabolic rates but have generally focused on whole brain lobes or geometrically derived regions of interest. In this report, a template of Brodmann areas, derived from a whole brain histological section atlas, was used to analyze PET findings from 34 AD patients and 16 control subjects matched for age, sex, and educational level. AD patients had lowest glucose metabolic rates in limbic areas of the temporal lobe and other proisocortical areas higher rates in frontal lobe and unimodal association areas, and relative sparing of parietal/occipital lobes and motor/sensory cortices. Analysis of variance revealed larger effect sizes when AD and control subjects were compared on metabolic rate for cortical type than for lobe. These findings, which parallel neuropathological studies of regional distribution of neurofibrillary tangles in AD, suggest that vulnerability is greatest in cortical areas that are in closer synaptic contact with limbic areas.

Spillantini, M. G. and M. Goedert (1998). "Tau protein pathology in neurodegenerative diseases." Trends Neurosci 21(10): 428-33.
Abundant tau-positive neurofibrillary lesions constitute a defining neuropathological characteristic of Alzheimer's disease. Filamentous tau pathology is also central to a number of other dementing disorders, such as Pick's disease, progressive supranuclear palsy, corticobasal degeneration and familial frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). The discovery of mutations in the tau gene in FTDP-17 has firmly established the relevance of tau pathology for the neurodegenerative process. Experimental studies have provided a system for the assembly of full-length tau into Alzheimer-like filaments, providing an assay for the testing of compounds that inhabit the formation of tau filaments.

Spillantini, M. G., R. A. Crowther, et al. (1998). "Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau." Am J Pathol 153(5): 1359-63.
Different mutations in the microtubule-associated tau protein gene have recently been identified in several families with hereditary frontotemporal dementia and Parkinsonism (FTDP-17) linked to chromosome 17q21-22. Some families show neuronal and glial deposits containing hyperphosphorylated tau in several brain regions. We have investigated the presence of tau deposits by using a panel of anti-tau antibodies in three brains of a family with the P301L mutation (HFTD1) and in another family with the G272V mutation (HFTD2) of the tau gene. Numerous intracytoplasmic tau deposits in neurons, glial cells, and neurites were found in hippocampal formation, neocortex, and substantia nigra. These deposits in three patients from HFTD1 consisted of slender twisted filaments 15 nm wide with variable periodicity and a few straight filaments. Tau extracted from these filaments appeared as two major bands of 64 and 68 kd and a minor band of 72 kd that, after alkaline phosphatase treatment, proved to consist mainly of 4-repeat tau isoforms and one of the 3-repeat isoforms. In three patients from HFTD2 numerous Pick-like bodies were present. The conclusion is that the type and distribution of tau deposits in HFTD1 and HFTD2, the physical structure of filaments, and tau isoform composition in HFTD1 differ from Alzheimer's disease and an FTDP-17 family with a V337M mutation in the tau gene.

Sparks, D. L., T. G. Beach, et al. (1998). "Immunohistochemical localization of nicotinic beta2 and alpha4 receptor subunits in normal human brain and individuals with Lewy body and Alzheimer's disease: preliminary observations." Neurosci Lett 256(3): 151-4.
Optimum immunohistochemical methods were established to immuno-localize nicotinic acetylcholine receptor alpha4 and beta2 subunits in temporal cortex and substantia nigra of normal aged and diseased human brain. In normal aged brain, fibers were immunoreactive for both the alpha4 and beta2 subunits of the nicotinic receptor in the temporal cortex and the substantia nigra. In the cortex of normal aged brain, rare neurofibrillary tangles occurring could be identified with either anti-alpha4 or anti-beta2 antibodies, but existing senile plaques were demonstrable with neither. In Alzheimer's disease temporal cortex, there were diminished numbers of nicotinic receptor subunit immunoreactive fibers, and there were appreciable numbers of neuropil threads, neurofibrillary tangles and senile plaques immunoreactive with both the alpha4 and beta2 antibodies.

Sodeyama, N., Y. Itoh, et al. (1998). "Presenilin 1 intronic polymorphism is not associated with Alzheimer type neuropathological changes or sporadic Alzheimer's disease." J Neurol Neurosurg Psychiatry 64(4): 548-51.
BACKGROUND: A genetic association between the presenilin 1 (PS-1) intronic polymorphism and sporadic Alzheimer's disease has been a matter of controversy. Recent findings have suggested that the PS-1 polymorphism is not associated with Alzheimer's disease or amyloid beta-protein (Abeta) deposition in brains from patients with Alzheimer's disease. OBJECTIVES: To elucidate the influence of the PS-1 polymorphism on Alzheimer type neuropathological changes and the development of Alzheimer's disease, the relation between the PS-1 polymorphism and quantitative severity of Alzheimer type neuropathological changes in the brains from patients with Alzheimer's disease and non-demented subjects was studied. METHODS: The PS-1 and apolipoprotein E (ApoE) genotypes, were examined, together with the densities of the senile plaques, senile plaques with dystrophic neurites, and neurofibrillary tangles in the brains from 36 postmortem confirmed patients with sporadic Alzheimer's disease and 86 non-demented subjects. Association of the PS-1 polymorphism with sporadic Alzheimer's disease and ages at onset and duration of illness in Alzheimer's disease was also examined. RESULTS: The PS-1 polymorphism was not associated with the senile plaques, senile plaques with dystrophic neurites, or neurofibrillary tangles in Alzheimer's disease or non-demented subjects. There was no association of the PS-1 intronic polymorphism with Alzheimer's disease, ages at onset, or durations of illness in Alzheimer's disease. The results remained nonsignificant even when the PS-1 genotype groups were divided into the subgroups with different ApoE epsilon4 status. CONCLUSIONS: The PS-1 intronic polymorphism does not itself have a direct causal role in the formation of Alzheimer type neuropathological changes or in the development of sporadic Alzheimer's disease.

Smith, M. A., K. Wehr, et al. (1998). "Abnormal localization of iron regulatory protein in Alzheimer's disease." Brain Res 788(1-2): 232-6.
A role for altered iron metabolism in the pathogenesis of Alzheimer's disease has been suggested by several reports associating the cardinal neuropathologic lesions with markers of free radical-induced damage and redox-active iron. We hypothesized that the abnormal distribution of iron in Alzheimer brain might result from alterations in iron regulatory proteins (IRP) such as IRP-1 and IRP-2, the main control elements of cellular iron homeostasis. Here, we report that while IRP-1 is present at similar levels in both Alzheimer and control brain tissue, IRP-2 shows striking differences and is associated with intraneuronal lesions, including neurofibrillary tangles, senile plaque neurites and neuropil threads. Since IRP-2 colocalizes with redox-active iron, our results suggest that alterations in IRP-2 might be directly linked to impaired iron homeostasis in Alzheimer's disease.

Singleton, A. B., G. Smith, et al. (1998). "No association between the K variant of the butyrylcholinesterase gene and pathologically confirmed Alzheimer's disease." Hum Mol Genet 7(5): 937-9.
The polymorphic K variant of the butyrylcholinesterase ( BCHE-K ) gene recently has been demonstrated to have an elevated frequency in Alzheimer's disease (AD) patients carrying the epsilon4 allele of the apolipoprotein (APO E) gene when compared with a control population. We therefore genotyped a large series of pathologically confirmed AD patients and controls to confirm this association. We found no change in the frequency of this genetic variant, either in the AD group as a whole or in early- or late-onset patients when compared with age-matched controls. Stratification of these groups with reference to the APO E epsilon4 allele also showed no difference between AD and control groups. To determine if a biological effect were present, we also looked at senile plaque and neurofibrillary tangle densities in the frontal, temporal, parietal and occipital cortices in AD patients either carrying or not carrying a copy of the K variant. We found no difference in plaque or tangle load between these two groups in either the total, late-onset or early-onset AD subjects. Stratification of the total AD group in terms of APO E epsilon4 allele possession, and further comparison of plaque and tangle load between carriers and non-carriers of BCHE-K still failed to disclose a relationship between BCHE-K and AD. We conclude that in the population studied here there is no association between BCHE-K and AD, or that if such a relationship exists it is precluded by another, as yet unknown factor.

Singhrao, S. K., P. Thomas, et al. (1998). "Huntingtin protein colocalizes with lesions of neurodegenerative diseases: An investigation in Huntington's, Alzheimer's, and Pick's diseases." Exp Neurol 150(2): 213-22.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease associated with a CAG trinucleotide repeat expansion in a large gene on chromosome 4. The gene encodes the protein huntingtin with a polyglutamine tract encoded by the CAG repeat at the N-terminus. The number of CAG repeats in HD are significantly increased (36 to 120+) compared with the normal population (8-39). The pathological mechanism associated with the expanded CAG repeat in HD is not clear but there is evidence that polyglutamine is directly neurotoxic. We have immunolocalized huntingtin with an in-house, well-characterised, polyclonal antibody in HD, Alzheimer's disease (AD), and Picks disease (PiD) brains. Control brain tissue sections were from head injured and cerebral ischaemia cases. In HD, huntingtin was immunopositive in the surviving but damaged neurons and reactive astrocytes of the caudate and putamen. However, in AD and PiD the immunostaining was largely restricted to the characteristic intracellular inclusion bodies associated with the disease process in each case. In AD, huntingtin was localized only in the intracellular neurofibrillary tangles and dystrophic neurites within the neuritic amyloid plaques but not with the amyloid. In PiD, strongly positive huntingtin immunostaining was present within cytoplasmic Pick bodies. Our findings suggest huntingtin selectively accumulates in association with abnormal intracytoplasmic and cytoskeletal filaments of neurons and glia in neurodegenerative diseases such as HD, AD, and PiD. Cells in the CNS appear sensitive to damage by the aggregated, toxic levels of huntingtin and evidence of its interaction with neurofilaments could provide information about its potential role in the aetiology of HD.

Silver, M., K. Newell, et al. (1998). "Unraveling the mystery of cognitive changes in old age: correlation of neuropsychological evaluation with neuropathological findings in the extreme old." Int Psychogeriatr 10(1): 25-41.
In order to understand what cognitive changes can be expected with aging versus those caused by disease, the New England Centenarian Study examined correlations between neuropsychological evaluation and neuropathological studies of centenarian subjects. Sixty-nine subjects were administered an extensive neuropsychological test battery designed for centenarians. Six brain donors from this group have subsequently died, and neuropathological studies of their brains have been performed to determine the presence of Alzheimer's disease (AD) and other pathological states. Of these six centenarians, three subjects had Clinical Dementia Rating scores of 0 and no dementia on neuropsychological testing, and subsequent neuropathology showed very limited AD changes. In fact, despite a range of neuropsychological findings, none of the subjects in this series met neuropathological criteria for a diagnosis of definite AD. Findings suggest that dementia is not inevitable with aging and that dementia in this age group is surprisingly often not attributable to AD.

Sheng, J. G., R. E. Mrak, et al. (1998). "Progressive neuronal DNA damage associated with neurofibrillary tangle formation in Alzheimer disease." J Neuropathol Exp Neurol 57(4): 323-8.
DNA damage, as demonstrated by in situ Tdt-mediated dUTP-X-nick end labeling (TUNEL), is widespread in the cerebral cortex in end-stage Alzheimer disease, but has not been previously correlated with stages of neurofibrillary tangle formation. To assess possible relationships between neurofibrillary tangle formation and DNA damage, we used tau immunohistochemistry and TUNEL in tangle-rich fields of tissue sections of subiculum and parahippocampal cortex tissue from 12 Alzheimer and 6 control patients. Structures were classified and quantified as tau-/TUNEL-, tau-/TUNEL+, tau+/TUNEL-, or tau+/TUNEL+. Tau+ structures were subclassified into 4 stages (0-3) based on neurofibrillary tangle morphology. The total number of TUNEL+ neurons was significantly less in control than in Alzheimer patients (35 +/- 7.2 vs 90 +/- 9.3/mm2; mean +/- SEM; p < 0.05). The number of tau+/TUNEL+ neurons (40 +/- 1/mm2) was less than that of tau-/TUNEL- neurons (68 +/- 7/mm2) or tau-/TUNEL+ neurons in the same fields (50 +/- 4/mm2, p < 0.0001). Tau+/TUNEL- structures were fewer in number (21 +/- 1/mm2), with a third of these representing acellular "ghost tangles" (stage 3). Tau+ neurons were more likely than tau- neurons to be TUNEL+ (64 +/- 6% vs 44 +/- 2%; mean +/- SEM; p < 0.01), although most TUNEL+ neurons were tau-, even in these selected, tangle-rich fields. TUNEL positivity was not uniformly distributed among tangle stages. TUNEL positivity was less common among early (stage 0) tangles than in tau neurons (21 +/- 6% vs 44 +/- 2%; p < 0.001), but this rose to 53% among intermediate (stage 1) tangles, and to 87% among late (stage 2) tangles. We suggest that early stages of neurofibrillary tangle formation occur in a subpopulation of relatively healthy (TUNEL-) neurons, and that tangle progression is accompanied by increasing neuronal morbidity.

Sheng, J. G., R. E. Mrak, et al. (1998). "Enlarged and phagocytic, but not primed, interleukin-1 alpha-immunoreactive microglia increase with age in normal human brain." Acta Neuropathol (Berl) 95(3): 229-34.
Microglia-mediated inflammatory responses have been implicated in the pathogenesis of neuritic plaques in Alzheimer's disease. The strong age association of Alzheimer's disease incidence suggests that events in normal aging may promote such responses. We used immunohistochemistry and computerized image analysis to determine the numbers, size, activation state, and immunoreactive intensity of interleukin-1 alpha-immunoreactive (IL-1 alpha +) microglia in mesial temporal lobe of 20 neurologically normal individuals, 2-80 years of age. We also used Northern analysis to determine tissue levels of IL-1 alpha mRNA in an additional 11 neurologically normal individuals aged 1 day to 78 years. IL-1 alpha + microglia were characterized as primed, enlarged, or phagocytic (enlarged with heterogeneous cytoplasmic contents) based on morphology. These three microglial subtypes showed significant differences in size [27 +/- 1 58 +/- 2 114 +/- 6 (mean +/- SEM) micron 2/cell, respectively, P < 0.001 for each comparison] and in immunoreactive intensity [60 +/- 1 68 +/- 2 79 +/- 2 (arbitrary units), respectively, P < 0.001 or better for each comparison]. There were significant age-associated increases in the total numbers of activated IL-1 alpha + microglia. Among microglial subtypes, there were significant increases in the numbers of enlarged (threefold) and especially phagocytic (elevenfold), but not primed, microglia. Tissue IL-1 alpha mRNA levels were higher in individuals over 60 than in those less than 60 (P < 0.05). The age-associated increases in microglial activation were independent of postmortem interval, patient sex, and the presence of Alzheimer-type 'senile' changes. Age-associated increases in microglial activation and IL-1 expression may contribute to the age-associated increased risk of Alzheimer's disease.

Schwab, C. and P. L. McGeer (1998). "Tubulin immunopositive structures resembling intracellular neurofibrillary tangles." Neurobiol Aging 19(1): 41-5.
Tau protein promotes microtubule assembly. When aberrantly phosphorylated, it forms the core of neurofibrillary tangles (NFTs). We investigated by immunohistochemistry whether microtubules might also be involved in NFT formation. We found beta-tubulin immunoreactive NFT-like structures in Alzheimer disease, and, more frequently, in the parkinsonism dementia complex of Guam (bodig disease) and Down Syndrome. The beta-tubulin immunoreactive structures were intracellular and appeared at an early stage of tangle development. This may indicate an involvement of tubulin in NFT formation.

Schwab, C., J. C. Steele, et al. (1998). "Pyramidal neuron loss is matched by ghost tangle increase in Guam parkinsonism-dementia hippocampus." Acta Neuropathol (Berl) 96(4): 409-16.
The parkinsonism dementia complex of Guam (bodig disease) is characterized by severe neurofibrillary tangle (NFT) development without the senile plaques which characterize Alzheimer's disease. Here we analyze eight cases of bodig and three control cases from Guam, for the numbers of unaffected pyramidal neurons, intracellular NFTs (iNFTs), and extracellular NFTs (eNFTs) in hippocampal sectors CA1 and CA4. We utilized Alz50 immunostaining to identify iNFTs, amyloid P immunostaining to identify eNFTs, and cresyl violet staining to identify the surviving pyramidal neurons. We developed a modification of the Bielschowsky silver staining method which distinguished iNFTs from eNFTs and found the numbers of iNFTs and eNFTs identified by this method to be comparable to those obtained by immunohistochemical staining. In CA4, the combined total of unaffected pyramidal neurons, iNFTs and eNFTs was found to be remarkably constant in all the cases studied. The density of eNFTs correlated significantly and negatively with the density of surviving neurons, which included unaffected neurons and iNFTs. CA1 was more intensely affected than CA4. The combined total of unaffected pyramidal neurons, iNFTs and eNFTs was still relatively constant, although greater variability was recorded. Our results suggest that loss of pyramidal neurons is proportional to the appearance of eNFTs. The eNFTs accumulate, without evidence of disappearance through phagocytosis.

Schwab, C., H. Akiyama, et al. (1998). "Extracellular neurofibrillary tangles are immunopositive for the 40 carboxy-terminal sequence of beta-amyloid protein." J Neuropathol Exp Neurol 57(12): 1131-7.
Neurofibrillary tangles (NFTs) form in a number of neurodegenerative disorders. In Alzheimer disease (AD), intracellular NFTs (iNFTs) develop along with extracellular beta-amyloid (Abeta) deposits. Reports on whether NFTs have Abeta associated with them are inconsistent. Here we study NFTs and their direct relationship with Abeta-like fragments in cases of AD, Down Syndrome, and the parkinsonism-dementia complex of Guam, using a panel of antibodies which recognize different epitopes of Abeta. In all diseases, as well as in the aged controls, the majority of extracellular NFTs (eNFTs) are stained with antibodies recognizing the 40 carboxy-terminal of Abeta, but not other epitopes. Such staining is morphologically distinguishable from the previously described Abeta positive 'tangle associated amyloid deposits' (TAADs), which surround some eNFTs, and are immunopositive for all epitopes of the Abeta molecule. Some iNFTs are immunoreactive with antibodies to the 42 carboxy-terminal epitope, and, to a lesser extent, with antibodies to midportions and more N-terminal epitopes of Abeta. These results may indicate a direct interaction between Abeta and NFTs, although secondary deposition or crossreactivity with other epitopes associated with NFTs cannot be ruled out.

Schulz, J. G., D. Megow, et al. (1998). "Evidence that glypican is a receptor mediating beta-amyloid neurotoxicity in PC12 cells." Eur J Neurosci 10(6): 2085-93.
Docking of beta-amyloid fibrils to neuronal or glial cell membranes may be an early, necessary and intervenable step during the progression of Alzheimer's disease. Formation of neurofibrillary tangles and amyloid plaques as well as neurotoxicity and inflammation may be direct or indirect consequences. In an attempt to find a receptor that mediates those effects, we assessed rat pheochromocytoma PC12 cell 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) reduction after addition of beta-amyloid to the culture medium. Presence of competitive substances in the medium, cell-surface treatment and specific block of cellular synthesis pathways helped to identify the heparan sulphate moiety of a glycosylphosphatidylinositol-anchored protein likely to represent glypican as a possible receptor mediating beta-amyloid neurotoxicity.

Schochet, S. S., Jr. (1998). "Neuropathology of aging." Neurol Clin 16(3): 569-80.
The brain undergoes many gross and histopathologic changes with advancing age. Some of the changes seen with aging are also found in demented individuals, especially patients with Alzheimer's disease. The extent to which Alzheimer's disease and aging are truly different processes remains to be determined. The morphologic features that seem most clearly to distinguish between aging and Alzheimer's disease are the neurofibrillary tangles and senile plaques. The distinction can be further refined by determining the immunocytochemical and ultrastructural composition of the degenerating nerve processes in the neuritic plaques.

Schneider, L. S. (1998). "Cholinergic deficiency in Alzheimer's disease. Pathogenic model." Am J Geriatr Psychiatry 6(2 Suppl 1): S49-55.
Genetic vulnerability factors are becoming more important in AD, yet only a minority of cases are familial, and of these only a portion are genetically determined. Because, early in the course, neurodegeneration is occurring in vulnerable cholinergically innervated regions and not throughout the brain as a whole, AD may be conceptualized as a corticolimbic system neurodegenerative disorder involving the entorhinal cortex, hippocampus, and amygdala. This conceptualization has obvious implications for the development of therapies since future interventions may be designed to prevent or slow neurodegeneration or improve clinical signs by modulating risk factors, beta-amyloid deposition, and phosphorylation of tau proteins; inhibiting inflammatory or oxidative processes; or enhancing cholinergic function in various ways. The recently reported effects of antioxidants, including vitamin E and selegiline, in prolonging time to institutionalization, death, or significant worsening, is one example of the feasibility of this approach, as are the observations that anti-inflammatory use may reduce AD risk and that long-term cholinesterase inhibitor use may delay nursing home placement. At present, approaches that are focused on neurotransmitter systems may prove more immediately accessible targets for therapeutic intervention.

Scheff, S. W. and D. A. Price (1998). "Synaptic density in the inner molecular layer of the hippocampal dentate gyrus in Alzheimer disease." J Neuropathol Exp Neurol 57(12): 1146-53.
We examined the inner molecular layer (IML) of the hippocampal dentate gyrus for possible changes in synaptic density. Material was obtained from 9 individuals with Alzheimer disease (AD) and compared to samples obtained from 10 age-matched, postmortem-matched neurologically normal controls, employing standard ultrastructural techniques. Statistical analyses demonstrated a significant decline in synaptic numbers between controls and AD subjects. This decline was accompanied by a significant increase in apposition length and resulted in a significant correlation with the synaptic density. As the number of synapses declined, the apposition length increased. Assessment was also made of the granule cells density and the analyses showed a significant decline in the synapse to granule cell ratio in the AD group. This decline in the density of synaptic contacts in the IML reflects a more widespread decline in plasticity in AD and may be related to the memory problems associated with the disease.

Savory, J., Y. Huang, et al. (1998). "Reversal by desferrioxamine of tau protein aggregates following two days of treatment in aluminum-induced neurofibrillary degeneration in rabbit: implications for clinical trials in Alzheimer's disease." Neurotoxicology 19(2): 209-14.
A clinical trial in patients with Alzheimer's disease has indicated that frequent intramuscular (i.m.) treatment with desferrioxamine (DFO) slows progression of the disease. Confirmatory trials have not been carried out, partly because of the rigors of twice daily intramuscular injections over a period of 2 years, even though the initial report gave promising results. The aim of the present study was to determine an optimal DFO treatment protocol in an animal model exhibiting Alzheimer's-like intraneuronal protein aggregates, previously shown to be partially reversed by such treatment. New Zealand white rabbits were injected intracisternally with either aluminum (Al) maltolate or with saline on day 0. Intramuscular injections of DFO were given to selected rabbits for 2 days prior to sacrifice on days 4, 6 or 8. Bielschowsky's silver impregnation demonstrated widespread neurofibrillary degeneration (NFD) in neuronal cell bodies and neurites of brain and spinal cord from Al-treated rabbits. Monoclonal antibodies Tau-2, AT8, PHF-1 and Alz-50, all of which characteristically stain neurofibrillary tangles associated with Alzheimer's disease, strongly labeled the Al-induced NFD. The number of positive neurons and staining intensities were much less in rabbits treated with Al and subsequently with DFO, than in animals only given Al. Control rabbit receiving intracisternal saline were negative for NFD. The results of quantitative immunohistochemistry using image analysis confirmed that immunostaining densities with all tau mAbs were higher in Al-treated than in Al-DFO-treated or in saline-treated controls. Furthermore, it appears that hyperphosphorylation of tau does not make this protein resistant to degradation once Al has been removed by DFO treatment. The effectiveness of only two days of DFO treatment in reversing Al-induced neurofibrillary degeneration suggests that further clinical trials of DFO for treatment of Alzheimer's disease should be attempted using much less frequent administration of DFO than in the initial study (Crapper McLachlan et al., 1991).

Savory, J. and R. M. Garruto (1998). "Aluminum, tau protein, and Alzheimer's disease: an important link?" Nutrition 14(3): 313-4.

Sasaki, N., R. Fukatsu, et al. (1998). "Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases." Am J Pathol 153(4): 1149-55.
Advanced glycation end products (AGEs) have been implicated in the chronic complications of diabetes mellitus and have been reported to play an important role in the pathogenesis of Alzheimer's disease. In this study, we examined the immunohistochemical localization of AGEs, amyloid beta protein (A beta), apolipoprotein E (ApoE), and tau protein in senile plaques, neurofibrillary tangles (NFTs), and cerebral amyloid angiopathy (CAA) in Alzheimer's disease and other neurodegenerative diseases (progressive supranuclear palsy, Pick's disease, and Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex). In most senile plaques (including diffuse plaques) and CAA from Alzheimer's brains, AGE and ApoE were observed together. However, approximately 5% of plaques were AGE positive but A beta negative, and the vessels without CAA often showed AGE immunoreactivity. In Alzheimer's disease, AGEs were mainly present in intracellular NFTs, whereas ApoE was mainly present in extracellular NFTs. Pick's bodies in Pick's disease and granulovacuolar degeneration in various neurodegenerative diseases were also AGE positive. In non-Alzheimer neurodegenerative diseases, senile plaques and NFTs showed similar findings to those in Alzheimer's disease. These results suggest that AGE may contribute to eventual neuronal dysfunction and death as an important factor in the progression of various neurodegenerative diseases, including Alzheimer's disease.

Samuels, S. C. and K. L. Davis (1998). "Experimental approaches to cognitive disturbance in Alzheimer's disease." Harv Rev Psychiatry 6(1): 11-22.
This paper reviews available and potential treatments for the cognitive disturbances associated with Alzheimer's disease. The neurochemical, neuropathological, and molecular-biological abnormalities associated with this disorder, as well as possible sites for pharmacological intervention, are discussed. These sites include genetic alterations in apolipoprotein E, amyloid precursor protein, and presenilin. Additionally, modification of amyloid processing, tau processing, and calcium regulation may have a role in future treatment. Intriguing epidemiological findings involving antiinflammatories, antioxidants, and estrogen for the cognitive deficits associated with Alzheimer's disease suggest the need for clinical trials of these agents. The current status of cholinesterase inhibitors, muscarinic receptor agonists, nicotine, and adrenergic and glutaminergic approaches to treatment are described.

Salehi, A., J. M. Bakker, et al. (1998). "Limited effect of neuritic plaques on neuronal density in the hippocampal CA1 area of Alzheimer patients." Alzheimer Dis Assoc Disord 12(2): 77-82.
Neurofibrillary tangles (NFTs) and neuritic plaques (NPs) are the classic neuropathological hallmarks of Alzheimer disease (AD). It is generally assumed that the pathogenic process of AD could start by local neurotoxicity induced by the beta-amyloid core of plaques, followed by the appearance of NFTs and eventually cell death. To determine whether or not local neurotoxicity around NPs is indeed a major pathogenetic mechanism, we used an image analysis system to measure the neuronal density around Bodian-stained NPs in the hippocampal CA1 area of eight AD patients. Neuronal density, as measured within two arbitrary concentric circles around NPs with a radius of 74 and 123.5 microm, respectively, was on average 19% and 16% lower than the density in similar control circles without NPs in the same section. Furthermore, neuronal density around NPs was inversely related to their size. To investigate the impact of such a local reduction in cell density around NPs on the entire CA1 area, we also determined the proportion of the CA1 covered by the NPs and the arbitrary concentric circles around them. This appeared to be 16.3% of the total CA1 area, which means that the negative effect of NPs on the cell density can only explain 2.6% of cell death in the entire CA area. In conclusion, this study suggests that although NPs have a local negative effect on neighboring neurons, their contribution to the strong decrease in CA1 cell numbers is limited.

Ray, W. J., F. Ashall, et al. (1998). "Molecular pathogenesis of sporadic and familial forms of Alzheimer's disease." Mol Med Today 4(4): 151-7.
Our understanding of the pathogenesis of Alzheimer's disease (AD) comes primarily from the study of rare inherited forms of the disease. Mutations that cause familial AD appear to act by a common mechanism: that of increasing production of A beta 42/43, one of the family of A beta peptides deposited in senile plaques. However, increased A beta 42/43 production has not been demonstrated to occur in most cases of sporadic AD, suggesting that genetic and environmental factors acting at other stages of the disease process can modify the risk for disease. Such factors most likely include those affecting A beta aggregation or clearance, the inflammatory response, cerebrovascular disease, or susceptibility of neurons to injury. Identifying these factors will lead to a better understanding of the etiology of the disease and provide additional targets for therapeutic intervention.

Purohit, D. P., D. P. Perl, et al. (1998). "Alzheimer disease and related neurodegenerative diseases in elderly patients with schizophrenia: a postmortem neuropathologic study of 100 cases." Arch Gen Psychiatry 55(3): 205-11.
BACKGROUND: Clinical studies suggest that severe cognitive impairment is common among elderly patients with schizophrenia who reside in long-stay psychiatric institutions; however, previous autopsy-based neuropathologic investigations have provided conflicting results about the occurrence of Alzheimer disease (AD) in elderly patients with schizophrenia. We report the results of a comprehensive neuropathologic study performed to identify AD and other dementing neurodegenerative diseases in elderly patients with schizophrenia. METHODS: A neuropathologic examination was performed on 100 consecutive autopsy brain specimens of patients aged 52 to 101 years (mean, 76.5 years). A cognitive assessment of these cases was also done by employing the Clinical Dementia Rating Scale. For comparison, we included 47 patients with nonschizophrenic psychiatric disorders from the same psychiatric hospital and 50 age-matched control subjects. RESULTS: Although 72% of the patients with schizophrenia showed cognitive impairment, AD was diagnosed in only 9% of the patients and other dementing diseases were diagnosed in only 4% of the patients. The degree of senile plaques or neurofibrillary tangles was not different in the group with schizophrenia compared with the age-matched controls or the group with nonschizophrenic psychiatric disorders. The higher Clinical Dementia Rating Scale scores lacked correlation with neuropathologic evidence of dementing disorders. In the 87 cases lacking a neuropathologic diagnosis of AD or other dementing disorders, the mean (+/-SD) Clinical Dementia Rating Scale score was 2.21 (+/-1.14), with 43 of the cases scoring 3 or higher (indicating severe, profound, or terminal cognitive impairment). CONCLUSIONS: This study provides evidence that elderly patients with schizophrenia are not inordinately prone to the development of AD or to increased senile plaques or neurofibrillary tangle formation in the brain. Other dementing neurodegenerative disorders are also uncommon. The cognitive impairment in elderly patients with schizophrenia must, therefore, be related to some alternative mechanisms.

Pratico, D., M. Y. L. V, et al. (1998). "Increased F2-isoprostanes in Alzheimer's disease: evidence for enhanced lipid peroxidation in vivo." Faseb J 12(15): 1777-83.
Alzheimer's disease (AD) includes a group of dementing neurodegenerative disorders that have diverse etiologies but the same hallmark brain lesions. Since oxidative stress may play a role in the pathogenesis of AD and isoprostanes are chemically stable peroxidation products of arachidonic acid, we measured both iPF2alpha-III and iPF2alpha -VI using gas chromatography-mass spectrometry in AD and control brains. The levels of both isoprostanes, but not of 6-keto PGF1alpha, an index of prostaglandin production, were markedly elevated in both frontal and temporal poles of AD brains compared to the corresponding cerebella. Levels were also elevated compared to corresponding areas of brains from patients who had died with schizophrenia or Parkinson's disease or from nonneuropsychiatric disorders. iPF2alpha -IV, but not iPF2alpha-III, levels were higher in ventricular CSF of AD brains relative to the non-AD brains. These data suggest that specific isoprostane analysis may reflect increased oxidative stress in AD.

Perl, D. P., C. W. Olanow, et al. (1998). "Alzheimer's disease and Parkinson's disease: distinct entities or extremes of a spectrum of neurodegeneration?" Ann Neurol 44(3 Suppl 1): S19-31.
Alzheimer's disease (AD) and Parkinson's disease (PD) are generally considered to be separate and distinct disease entities. However, a considerable amount of evidence demonstrates that these disorders share common clinical and neuropathologic features and that overlap between the two conditions is extensive. For example, a significant percentage of AD patients exhibit extrapyramidal features, and many PD patients develop dementia. Similarly, at autopsy many AD patients not only exhibit the neuropathologic features of that disorder but also exhibit nigral pathology, including Lewy bodies. The vast majority of demented PD patients show widespread neurofibrillary tangles and senile plaques as well as Lewy body formation and nigral degeneration. The extent of such overlap is far greater than one would anticipate by chance alone. We argue that such overlap reflects a common pathogenic mechanism for the neurodegeneration encountered within specific vulnerable neuronal populations. Furthermore, we suggest that the current nosologic approach, which attempts to separate AD from PD, fails to properly deal with the issue of overlap and that a new classification of the neurodegenerative disorders should be considered.

Pei, J. J., I. Grundke-Iqbal, et al. (1998). "Accumulation of cyclin-dependent kinase 5 (cdk5) in neurons with early stages of Alzheimer's disease neurofibrillary degeneration." Brain Res 797(2): 267-77.
Cyclin-dependent kinase 5 (cdk5) is one of the candidate kinases involved in the abnormal hyperphosphorylation of tau. To have a direct effect on tau hyperphosphorylation, cdk5 protein levels and enzyme activity should be upregulated in especially those neurons that develop neurofibrillary tangles (NFTs). We studied the distribution of cdk5 immunoreactivity in neurons with or without early- and late-stage NFTs in hippocampal, entorhinal, transentorhinal, temporal and frontal cortices, and cerebellum of Alzheimer's disease (AD) and control brain. The immunocytochemical localisation of cdk5 was compared with that obtained using antibodies to PHF-tau (tau in paired helical filaments of NFTs, mAb AT8) and ubiquitin as markers of early and late stage NFTs, respectively. Immunoreactivities of cdk5 and PHF-tau were found in neuronal perikarya and processes of hippocampal, entorhinal, transentorhinal, temporal and frontal, and cerebellar cortices. An apparent increase of cdk5 immunoreactivity was seen in pretangle neurons and in neurons bearing early stage NFTs. These findings suggest that this kinase might be involved in the formation of NFTs at a relatively early stage in the neocortex.

Pappolla, M., P. Bozner, et al. (1998). "Inhibition of Alzheimer beta-fibrillogenesis by melatonin." J Biol Chem 273(13): 7185-8.
It is generally postulated that the amyloid beta protein (Abeta) plays a central role in the progressive neurodegeneration observed in Alzheimer's disease. Important pathologic properties of this protein, such as neurotoxicity and resistance to proteolytic degradation, depend on the ability of Abeta to form beta-sheet structures or amyloid fibrils. We report that melatonin, a hormone recently found to protect neurons against Abeta toxicity, interacts with Abeta1-40 and Abeta1-42 and inhibits the progressive formation of beta-sheets and amyloid fibrils. These interactions between melatonin and the amyloid peptides were demonstrated by circular dichroism and electron microscopy for Abeta1-40 and Abeta1-42 and by nuclear magnetic resonance spectroscopy for Abeta1-40. Inhibition of beta-sheets and fibrils could not be accomplished in control experiments when a free radical scavenger or a melatonin analog were substituted for melatonin under otherwise identical conditions. In sharp contrast with conventional anti-oxidants and available anti-amyloidogenic compounds, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential new therapeutic agent in Alzheimer's disease.

Pallares-Trujillo, J., F. J. Lopez-Soriano, et al. (1998). "The involvement of the ubiquitin system in Alzheimer's disease (review)." Int J Mol Med 2(1): 3-15.
Alzheimer's disease, the most common form of senile dementia, affects more than 15 million people world-wide and is characterized by a marked deterioration in memory and all cognitive functions, as a result of a progressive degeneration and loss of cortical and limbic neurons. This process is associated with the presence of both the so-called -amyloid deposits and the cellular neurofibrillary tangles composed mainly of paired helical filaments of aberrantly hyperphosphorylated tau protein. The accumulation of ubiquitin in neurofibrillary tangles and senile plaques (both characteristic of the neuronal abnormalities associated with the disease) is postulated to play a role in the repair mechanism related to neuronal regeneration.

Oka, M., S. Katayama, et al. (1998). "Argyrophilic structures stimulate glial reactions in neurofibrillary tangles and senile plaques." Neurol Res 20(2): 121-6.
Neurofibrillary tangles (NFT) and senile plaques (SP) contain various pathological structures, and the majority of these pathological structures are argyrophilic. To investigate the glial reactions of the argyrophilic substance, we performed immunohistochemistry for microglia or for astroglia after Gallyas-Braak staining, which is one of the most sensitive silver impregnation techniques detecting argyrophilic structures in NFT and SP. We found that extracellular argyrophilic structures in NFT and SP showed glial reactions, and we observed reactive microglia in the center of NFT and SP in contrast to astroglia, which were situated in the periphery. These findings suggest that the exposed argyrophilic components in the extracellular space stimulate both glial reactions, but that there is a striking difference in localization between microglia and astroglia.

Nochlin, D., T. D. Bird, et al. (1998). "Amyloid angiopathy in a Volga German family with Alzheimer's disease and a presenilin-2 mutation (N141I)." Ann Neurol 43(1): 131-5.
We report the neuropathological features in 6 members of a Volga German family with autosomal dominant Alzheimer's disease linked to chromosome 1 who had a presenilin-2 mutation (N141I). The most significant feature in this family was the presence of severe or moderately severe amyloid angiopathy in five family members with clinical dementia. The index case with the presenilin-2 mutation had late-onset dementia at age 73 years, died of an acute intracerebral hemorrhage, and pathologically showed severe amyloid angiopathy but only rare neuritic senile plaques and neurofibrillary tangles. That she was apolipoprotein E epsilon2/3 heterozygous suggests that the epsilon2 allele may have exerted a selective protective effect resulting in late onset relatively mild Alzheimer's disease despite severe amyloid angiopathy. This family emphasizes the need for more investigation into the role of presenilin mutations in amyloid deposition, especially in the cerebral vasculature, and the role of these changes in clinical dementia.

Niizato, K., T. Arai, et al. (1998). "Autopsy study of Alzheimer's disease brain pathology in schizophrenia." Schizophr Res 31(2-3): 177-84.
The brains of 125 schizophrenic patients (DSM-IV criteria) without other major diseases likely to affect brain morphology were examined at autopsy in our hospital for an evaluation of the number of neurofibrillary tangles (NFT) and senile plaques (SP) as indicators of the incidence of Alzheimer's disease (AD) brain pathology. The clinical degree of dementia and the presence or absence of delirium and Parkinsonism were determined in a review of the patients' charts. No significant difference in the degree of AD brain pathology between the 12 schizophrenics more than 75 years old and 12 age-matched normal controls was present. We conclude that AD pathology seems to be no more frequent among schizophrenic patients than in the normal population, and that the severe cognitive impairment observed in schizophrenics is based on neither neuronal degeneration nor neuronal loss like that occurring in AD. We believe that future morphological studies of cognitive impairments in schizophrenics will require a more detailed investigation at the receptor level.

Neve, R. L. and N. K. Robakis (1998). "Alzheimer's disease: a re-examination of the amyloid hypothesis." Trends Neurosci 21(1): 15-9.
Alzheimer's disease (AD) is a neurodegenerative disorder of the brain characterized by the presence of neuritic amyloid plaques and neurofibrillary tangles. Although it most frequently occurs in the elderly, this disorder also afflicts younger patients. The majority of AD cases are late in onset, lack an obvious genetic etiology and are characterized as sporadic, whereas a small percentage of cases are early in onset and segregate strongly within families (FAD), suggesting a genetic etiology. During the past decade it has become evident that the clinical and histopathological phenotypes of this disease are caused by heterogeneous genetic, and probably environmental, factors. Indeed, several genes have been identified that together appear to cause most of the familial forms of the disease, whereas the epsilon4 allele of the apolipoprotein E (apoE) gene has been shown to be a significant risk factor for the late onset forms of AD. Despite this evidence of heterogeneity, it has been suggested that all of these factors work through a common pathway by triggering the deposition of amyloid in the brain, which is ultimately responsible for the neuronal degeneration of AD. This is a controversial theory, however, primarily because there is a poor correlation between the concentrations and distribution of amyloid depositions in the brain and several parameters of AD pathology, including degree of dementia, loss of synapses, loss of neurons and abnormalities of the cytoskeleton.

Nakamura, S., K. Arima, et al. (1998). "Fibroblast growth factor (FGF)-9 immunoreactivity in senile plaques." Brain Res 814(1-2): 222-5.
We examined fibroblast growth factor (FGF)-9 immunoreactivity in human hippocampal sections of Alzheimer's disease (AD). FGF-9 immunoreactivity was observed in dystrophic neurites of senile plaques in AD and control cases, in addition to the hippocampal and cortical neurons. The amyloid core and neurofibrillary tangles lacked immunoreactivity. FGF-9 immunoreactive astrocytes were conspicuous in AD brains. FGF-9 may be involved in the neuropathology of AD.

Nagy, Z., M. M. Esiri, et al. (1998). "Accuracy of clinical operational diagnostic criteria for Alzheimer's disease in relation to different pathological diagnostic protocols." Dement Geriatr Cogn Disord 9(4): 219-26.
In this study we analysed the accuracy of two sets of clinical diagnostic criteria, the NINCDS/ADRDA and DSM-III-R, in relation to the currently used pathological diagnostic criteria for Alzheimer's disease (AD), the Khachaturian criteria, the Tierney A3 criteria and the CERAD protocol. The sensitivity of the individual clinical diagnostic criteria, NINCDS/ADRDA and DSM-III-R, is poor (34-58%) irrespective of the pathological diagnostic criteria applied for the definite diagnosis of AD. The combination of the NINCDS/ ADRDA 'possible' and 'probable dementia of the Alzheimer type' (DAT) categories has a high sensitivity (91-98%). However the combination resulted in very poor specificity (40-61 %). Thus, none of the clinical diagnostic criteria is satisfactory. We found similar results when we analysed the predictive value of these clinical diagnostic criteria. The positive predictive value of NINCDS 'probable DAT' category and that of the DAT diagnosis by DSM-III-R is very high (89-100%). This makes the use of these categories suitable for research purposes. However, the negative predictive value of both diagnoses is poor (33-63%), making these criteria unsuitable for diagnostic purposes in clinical practice.

Nagy, Z., M. M. Esiri, et al. (1998). "Comparison of pathological diagnostic criteria for Alzheimer disease." Alzheimer Dis Assoc Disord 12(3): 182-9.
Because the clinical picture of Alzheimer disease (AD) is often difficult to discriminate from other dementing illnesses, the diagnosis of AD requires neuropathological confirmation. However, for the pathological diagnosis of AD, there are no unanimously accepted criteria. The three currently used sets of pathological criteria (Khachaturian: Khachaturian, Arch Neurol 1985;42:1097-105; Tiemy: Tierney et al., Can J Neurol Sci 1986; 13:424-6; CERAD: Mirra et al., Neurology 1991;41:479-86) for the disease differ from each other considerably. We applied these criteria to the first 43 consecutive subjects (37 demented) with no neuropathology other than AD-type pathology from autopsies after longitudinal prospective clinical study in the Oxford Project to Investigate Memory and Ageing (OPTIMA). The results show that the CERAD category of definite AD corresponds closely with the cases that fulfill Tierney A3 inclusion criteria for AD. The combined CERAD categories of possible, probable, and definite AD correspond closely to cases fulfilling Khachaturian criteria forAD. The influence of a clinical diagnosis of dementia when Khachaturian and CERAD criteria were applied was considerable because between 9.3% and 90.7% of patients would have been categorized differently depending on whether clinical dementia was present or absent.

Murthy, S. N., J. H. Wilson, et al. (1998). "Cross-linking sites of the human tau protein, probed by reactions with human transglutaminase." J Neurochem 71(6): 2607-14.
A portion of the neurofibrillary tangles of Alzheimer's disease has the characteristics of cross-linked protein. Because the principal component of these lesions is the microtubule-associated protein tau, and because a major source of cross-linking activity within neurons is supplied by tissue transglutaminase (TGase), it has been postulated that isopeptide bond formation is a major posttranslational modification leading to the formation of insoluble neurofibrillary tangles. Here we have mapped the sites on two isoforms of human tau protein (tau23 and tau40) capable of participating in human TGase-mediated isopeptide bond formation. Using dansyl-labeled fluorescent probes, it was shown that eight Gln residues can function as amine acceptor residues, with two major sites being Gln351 and Gln424. In addition, 10 Lys residues were identified as amine donors, most of which are clustered adjacent to the microtubule-binding repeats of tau in regions known to be solvent accessible in filamentous tau. The distribution of amine donors correlated closely with that of Arg residues, suggesting a link between neighboring positive charge and the TGase selectivity for donor sites in the protein substrate. Apart from revealing the sites that can be cross-linked during the TGase-catalyzed assembly of tau filaments, the results suggest a topography for the tau monomers so assembled.

Muramori, F., K. Kobayashi, et al. (1998). "A quantitative study of neurofibrillary tangles, senile plaques and astrocytes in the hippocampal subdivisions and entorhinal cortex in Alzheimer's disease, normal controls and non-Alzheimer neuropsychiatric diseases." Psychiatry Clin Neurosci 52(6): 593-9.
The present quantitative study was performed in order to discriminate pathological substrates for dementia from Alzheimer changes in normal controls (NC) and non-Alzheimer neuropsychiatric diseases (NAND). Regional densities of senile plaques (SP), neurofibrillary tangles (NFT) and astrocytes in the cornu ammonis (CA), subiculum and entorhinal cortex were measured and differences in these densities among Alzheimer's disease (AD), NAND and NC were statistically compared. Densities of NFT in the CA and subiculum were significantly higher in AD than in NAND, and densities of SP in all regions were significantly higher in AD than in NAND. Similarly, NFT density in the subiculum and SP density in all regions were higher in AD than in NC. Regional densities of astrocytes in most regions were closely correlated with those of Alzheimer changes. In conclusion, the attribution of the Alzheimer changes, particularly of NFT, to dementia is neglected when they are confined to the entorhinal cortex. However, the attribution of the Alzheimer changes to dementia should be appreciated when they spread from the entorhinal cortex to the subiculum and/or CA.

Munch, G., A. M. Cunningham, et al. (1998). "Advanced glycation endproducts are associated with Hirano bodies in Alzheimer's disease." Brain Res 796(1-2): 307-10.
One of the structural posttranslational modifications contributing to the formation of insoluble, and protease-resistant protein deposits in Alzheimer's disease (AD), such as neurofibrillary tangles (NFT) and beta-amyloid plaques are 'advanced glycation endproducts' (AGE). Using a polyclonal antibody against AGE in frozen sections of fixed brain tissue from Alzheimer's disease patients, AGE were identified in a further characteristic protein deposit in AD, namely in Hirano bodies. AGE are localized to ovoid, spherical, and rod-like Hirano bodies in the hippocampus, particularly numerous in the stratum lacunosum-moleculare of CA1. Since Hirano bodies are known to contain mainly cytoskeletal and cytoplasmic components and are localized within the soma of neurons our study suggests that AGE formation and intracellular protein crosslinking represent early stages during neuronal degeneration.

Munch, G., R. Schinzel, et al. (1998). "Alzheimer's disease--synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts." J Neural Transm 105(4-5): 439-61.
Many approaches have been undertaken to understand Alzheimer's disease (AD) but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, there is increasing evidence that the previously so-called "secondary factors" such as a disturbed glucose metabolism, oxidative stress and formation of "advanced glycation endproducts" (AGEs) and their interaction in a vicious cycle are also important for the onset and progression of AD. AGEs are protein modifications that contribute to the formation of the histopathological and biochemical hallmarks of AD: amyloid plaques, neurofibrillary tangles and activated microglia. Oxidative modifications are formed by a complex cascade of dehydration, oxidation and cyclisation reactions, subsequent to a non-enzymatic reaction of sugars with amino groups of proteins. Accumulation of AGE-crosslinked proteins throughout life is a general phenomenon of ageing. However, AGEs are more than just markers of ageing since they can also exert adverse biologic effects on tissues and cells, including the activation of intracellular signal transduction pathways, leading to the upregulation of cytokine and free radical production (oxidative stress). Oxidative stress is involved in various divergent events leading to cell damage, including an increase in membrane rigidity, DNA strand breaks and an impairment in glucose uptake. In addition, other age-related metabolic changes such as depletion of antioxidants or decreased energy production by a disturbed glucose metabolism diminish the ability of the cell to cope with the effects of radical-induced membrane, protein and DNA damage. With our improving understanding of the molecular basis for the clinical symptoms of dementia, it is hoped that the elucidation of the etiologic causes, particularly the positive feedback loops involving radical damage and a reduced glucose metabolism, will help to develop novel "neuroprotective" treatment strategies able to interrupt this vicious cycle of oxidative stress and energy shortage in AD.

Montine, K. S., E. Reich, et al. (1998). "Distribution of reducible 4-hydroxynonenal adduct immunoreactivity in Alzheimer disease is associated with APOE genotype." J Neuropathol Exp Neurol 57(5): 415-25.
Two major risk factors for late-onset familial and sporadic Alzheimer disease (AD), a leading cause of dementia worldwide, are increasing age and inheritance of the epsilon4 allele of the apolipoprotein E gene (APOE4). Several isoform-specific effects of apoE have been proposed; however, the mechanisms by which apoE isoforms influence the pathogenesis of AD are unknown. Also associated with AD is increased lipid peroxidation in the regions of the brain most damaged by disease. 4-hydroxynonenal (HNE), the most potent neurotoxic product of lipid peroxidation, is thought to be deleterious to cells through reactions with protein nucleophiles. We tested the hypothesis that accumulation of the most common forms of HNE-protein adducts, borohydride-reducible adducts, is associated with AD and examined whether there was a relationship to APOE. Our results demonstrated that reducible HNE adducts were increased in the hippocampus, entorhinal cortex, and temporal cortex of patients with AD. Furthermore, our data showed that the pattern of reducible HNE adduct accumulation was related to APOE genotype; AD patients homozygous for APOE4 had pyramidal neuron cytoplasmic accumulation of reducible HNE adducts, while AD APOE3 homozygotes had both pyramidal neuron and astrocyte accumulation of reducible HNE adducts. This is in contrast to our previous observations that a distinct HNE protein adduct, the pyrrole adduct, accumulates on neurofibrillary tangles in AD patients. We conclude that APOE genotype influences the cellular distribution of increased reducible HNE adduct accumulation in AD.

Mokhtari, K., T. Uchihara, et al. (1998). "Atypical neuronal inclusion bodies in meningioangiomatosis." Acta Neuropathol (Berl) 96(1): 91-6.
A case of meningioangiomatosis not associated with neurofibromatosis 2 in a 24-year-old man is reported. Abundant neurofibrillary tangles and threads, shown by immunohistochemistry and ultrastructural analysis to be similar to those seen in Alzheimer's disease, were found in the residual neuropil. Another lesion consisting of argyrophilic globular inclusion bodies with radial fibrils was found at the periphery. Single and double immunostaining with a panel of antibodies showed similarities between these inclusions and Pick bodies.

Moechars, D., K. Lorent, et al. (1998). "Transgenic mice expressing an alpha-secretion mutant of the amyloid precursor protein in the brain develop a progressive CNS disorder." Behav Brain Res 95(1): 55-64.
Expression of alpha-secretion mutant APP/RK in mouse brain results in a progressive disorganization of the central nervous system, exemplified by behavioral deficits, premature death and neuropathology. Here we report on the progressive nature of this CNS disorder as indicated by the age dependency of the neophobic reaction in the open-field test. The earlier reported NMDA hypo-sensitivity in the transgenic APP/RK mice is likely to represent a subtle functional disturbance, since no changes in NMDA receptor density or distribution could be detected. None of the typical neuropathological hallmarks of Alzheimer's Disease, i.e. amyloid deposits and neurofibrillary tangles are detected in the brain of these transgenic mice. Nevertheless, the progressive CNS disorder elicited in the transgenic APP/RK mice recapitulates certain features and symptoms of patients with Alzheimer's disease as discussed.

Miyakawa, T. (1998). "[Pathological changes of structure in the brain of Alzheimer's disease]." Tanpakushitsu Kakusan Koso 43(7): 875-8.

Miklossy, J., R. Kraftsik, et al. (1998). "Curly fiber and tangle-like inclusions in the ependyma and choroid plexus--a pathogenetic relationship with the cortical Alzheimer-type changes?" J Neuropathol Exp Neurol 57(12): 1202-12.
The question of whether thread- and tangle-like inclusions of the choroid plexus (known as Biondi inclusions) are related to the cortical lesions in Alzheimer disease (AD) has been debated for almost a century, yet remains unanswered. Recently beta-amyloid protein was biochemically isolated from the plexus, indicating a possible pathogenetic relationship between the degenerative changes of the cerebral cortex and those of the plexus. The goal of the present study was to analyze whether or not a significant correlation exists between the occurrence of the cortical AD-type changes and those in the ependyma and choroid plexus. In 292 consecutive autopsy cases several cortical areas, the ependyma, and the choroid plexus were analyzed to look for AD-type changes and Biondi inclusions using histochemical staining techniques and immunohistochemistry. A semiquantitative analysis of the density of cortical AD-type changes showed that of the 292 cases, 63 had severe cortical changes, 23 moderate changes, and 142 discrete changes. In 64 cases no plaques or neurofibrillary tangles were found. The number of cases with thread- and tangle-like elements in the plexus and ependyma was more than 96% in the 3 groups with cortical AD-type lesions, but low in the group without AD-type cortical changes (19%). The pathological argyrophilic filaments accumulating in the ependymal layer and plexus had histochemical properties of amyloid and were immunoreactive with antibodies to P component, ubiquitin, fibronectin and Tau protein. They did not react with antibodies to neurofilament proteins. Ultrastructurally, they consisted of densely packed straight and paired helical filaments and closely resembled neurofibrillary tangles and neuropil threads. The highly significant correlation (chi2, p = 0.001; R = 0.85) between the occurrence of AD-type changes in the cortex and those in ependyma and plexus suggests a pathogenetic relationship.

Michel, G., M. Mercken, et al. (1998). "Characterization of tau phosphorylation in glycogen synthase kinase-3beta and cyclin dependent kinase-5 activator (p23) transfected cells." Biochim Biophys Acta 1380(2): 177-82.
One of the histopathological markers in Alzheimer's disease is the accumulation of hyperphosphorylated tau in neurons called neurofibrillary tangles (NFT) composing paired helical filaments (PHF). Combined tau protein kinase II (TPK II), which consists of CDK5 and its activator (p23), and glycogen synthase kinase-3beta (GSK-3beta) phosphorylate tau to the PHF-form in vitro. To investigate tau phosphorylation by these kinases in intact cells, the phosphorylation sites were examined in detail using well-characterized phosphorylation-dependent anti-tau antibodies after overexpressing the kinases in COS-7 cells with a human tau isoform. The overexpression of tau in COS-7 cells showed extensive phosphorylation at Ser-202 and Ser-404. The p23 overexpression induced a mobility shift of tau, but most of the phosphorylation sites overlapped the endogenous phosphorylation sites. GSK-3beta transfection showed the phosphorylation at Ser-199, Thr-231, Ser-396, and Ser-413. Triplicated transfection resulted in phosphorylation of tau at 8 observed sites (Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-396, Ser-404, and Ser-413).

Michaelis, M. L., N. Ranciat, et al. (1998). "Protection against beta-amyloid toxicity in primary neurons by paclitaxel (Taxol)." J Neurochem 70(4): 1623-7.
Neurofibrillary tangles in Alzheimer's disease contain aggregates of abnormally phosphorylated microtubule-associated protein tau, indicating that microtubule breakdown is a primary event in the neurodegenerative cascade. Recent studies have shown that addition to neuronal cultures of amyloid peptides found in Alzheimer's leads to abnormal phosphorylation of tau and neurofibrillary pathology. We tested the possibility that the microtubule-stabilizing drug paclitaxel (Taxol) might protect primary neurons against amyloid-induced toxicity. Neurons exposed to aggregated amyloid peptides 25-35 and 1-42 became pyknotic with degenerating neurites within 24 h. Treatment of cultures with paclitaxel either 2 h before or 2 h after addition of the peptide prevented these morphological alterations. When numbers of viable cells were determined in cultures exposed to amyloid peptide with or without paclitaxel for 24 or 96 h, the percentage of surviving cells was significantly higher in paclitaxel-treated cultures, and activation of the apoptosis-associated protease CPP32 was significantly reduced. These observations indicate that microtubule-stabilizing drugs may help slow development of the neurofibrillary pathology that leads to the loss of neuronal integrity in Alzheimer's disease.

McLaurin, J., T. Franklin, et al. (1998). "Structural transitions associated with the interaction of Alzheimer beta-amyloid peptides with gangliosides." J Biol Chem 273(8): 4506-15.
Alzheimer's disease is characterized pathologically by the presence of neurofibrillary tangles and amyloid plaques. The principal component of the plaque is the beta-amyloid peptide (Abeta), a 39-43-residue peptide. The conformational change required for the conversion of soluble peptide into amyloid fibrils is modulated by pH, Abeta concentration, addition of kinetic and thermodynamic enhancers, and alterations in the primary sequence of Abeta. We report here the ability of gangliosides to induce an alpha-helical structure in Abeta and thereby diminish fibrillogenesis. Circular dichroism and a fluorescence dye release assay data indicate that gangliosides interact with and induce alpha-helix formation in Abeta. We find that the sialic acid moiety of gangliosides is necessary for the induction of alpha-helical structure. Differences in the amount and the position of the sialic acid on the carbohydrate backbone also affect the conformational switch. The Abeta-ganglioside interaction at pH 7.0, monitored by CD, is stable over time and resistant to high concentrations of NaCl. The induction of alpha-helical structure is greater with Abeta1-40 than Abeta1-42. The ability of gangliosides to sequester Abeta from fibril formation was also evaluated by electron microscopy.

McKeith, I. G., P. Ince, et al. (1998). "What are the relations between Lewy body disease and AD?" J Neural Transm Suppl 54: 107-16.
Several hospital based autopsy series indicate dementia with Lewy bodies (DLB) to be the second most common pathological subtype of degenerative dementia in elderly subjects. The majority of DLB cases have high densities of beta amyloid senile plaques, whereas neocortical neurofibrillary tangle density is only slightly increased above age-matched normal control values and over tenfold lower than the average in Alzheimer's disease. The interpretation of this Alzheimer type pathology is problematic, reflecting in part changing views about the neuropathological diagnosis of AD itself. AD is characterised by hyperphosphorylation of the microtubular associated protein tau, and DLB by neurofilament abnormalities including phosphorylation, ubiquitination, proteolysis, and cross-linking of constituent proteins. The two diseases appear therefore to be distinct at an ultrastructural and molecular level, a conclusion which is consistent with the fact that the clinical syndromes associated with DLB and AD are sufficiently differentiated to allow for accurate antemortem diagnosis.

Mattila, P. M., M. Roytta, et al. (1998). "Cortical Lewy bodies and Alzheimer-type changes in patients with Parkinson's disease." Acta Neuropathol (Berl) 95(6): 576-82.
We investigated the role of cortical Lewy bodies (LB) and Alzheimer-type changes in cognitive impairment in patients with idiopathic Parkinson's disease (PD). We evaluated 44 cases for the extent of neuropathological lesions with a CERAD neuropathological assessment battery and the stage of dementia using Reisberg's global deterioration scale (GDS). Substantia nigra, amygdala, hippocampus and cerebral cortex were examined for LB and Alzheimer-type changes. For detection of LB, the cortical areas were stained with polyclonal antibodies against ubiquitin and tau. We found at least one cortical LB in 93% of cases. Furthermore, 43% of the cases had histological findings of definite Alzheimer's disease (AD). The association between cognitive impairment and the number of cortical LB and Alzheimer-type changes in the amygdala, hippocampus and six selected gyri from cerebral cortex were analyzed using stepwise linear regression. In this analysis the total number of cortical LB, and the amount of neurofibrillary tangles in the temporal cortex remained statistically significant. When the cases with neuropathological changes consistent with a diagnosis of AD were excluded, the correlation between the total number of cortical LB and cognitive impairment was more obvious. A stepwise linear regression analysis in these cases found the total number of cortical LB to be the statistically significant predictor of cognitive impairment. This study revealed that LB densities in the cortex, especially in the temporal neocortex, correlated significantly with the cognitive impairment in PD independent of or in addition to Alzheimer-type pathology.

Mann, D. M., S. M. Brown, et al. (1998). "Amyloid beta protein (A beta) deposition in dementia with Lewy bodies: predominance of A beta 42(43) and paucity of A beta 40 compared with sporadic Alzheimer's disease." Neuropathol Appl Neurobiol 24(3): 187-94.
Amyloid beta protein (A-beta) deposition was investigated by quantitative immunohistochemistry in 13 cases of dementia with Lewy bodies (DLB) and compared with that in a series of age, gender and ApoE genotype matched cases of Alzheimer's disease (AD). In DLB the predominant A-beta peptide species deposited was A-beta-42(43) and this was similar in amount to that in AD. By contrast, A-beta(40) deposition was sparse in DLB and was lower than that in AD as was the total A-beta (A-beta-40 + A-beta-42(43) deposition. These data reinforce the viewpoint that in all disorders in which A-beta deposition is characteristics, the initial and predominant peptide species deposited is the longer form, A-beta-42(43). The density of Lewy bodies (LB) in DLB was unrelated to the extent of A-beta deposition, although those cases possessing one or more copies of the apolipoprotein E E4 allele had a higher LB density than those without an E4 allele. This suggests that the apolipoprotein E E4 isoform might facilitate, though not necessarily trigger, the formation of LB in susceptible individuals.

Makjanic, J., B. McDonald, et al. (1998). "Absence of aluminium in neurofibrillary tangles in Alzheimer's disease." Neurosci Lett 240(3): 123-6.
Using the new technique of nuclear microscopy, aluminium is not detected in pyramidal neurons in brain tissue from Alzheimer's disease (AD) patients. The analytical technique of nuclear microscopy can simultaneously image and analyse features in unstained and untreated tissue sections. In tissue which had been previously subjected to conventional procedures such as fixation and osmication, aluminium was observed in both neurons and surrounding tissue. This result shows that the analysis of tissue prepared using conventional chemical techniques may produce contamination or elemental redistribution, and supports our previous investigations which implied that aluminium is not involved in the aetiology of AD. In addition, significant increases in iron, phosphorus and sulphur concentrations were noted between neurons from Alzheimer tissue and neurons from age-matched controls, and between the supporting Alzheimer tissue and supporting control tissue, implying an overall increase in these elements. No significant increase in calcium was observed between neurons from Alzheimer tissue and neurons from age-matched controls.

Mailliot, C., N. Sergeant, et al. (1998). "Phosphorylation of specific sets of tau isoforms reflects different neurofibrillary degeneration processes." FEBS Lett 433(3): 201-4.
Tau proteins are the basic components of filaments that accumulate within neurons during neurofibrillary degeneration, a degenerating process with disease-specific phenotypes. This specificity is likely to be sustained by both phosphorylation state and isoform content of tau aggregates that form neuronal inclusions. In the present study, characterization of tau isoforms involved in neurofibrillary degeneration in Alzheimer's disease, Pick's disease, corticobasal degeneration and progressive supranuclear palsy was performed. Both analyses by immunoblotting using specific tau antibodies and cell transfection by tau isoform cDNAs allowed us to demonstrate the aggregation of (1) the six hyperphosphorylated tau isoforms in Alzheimer's disease, (2) tau isoforms without exon 10-encoding sequence in Pick's disease and (3) hyperphosphorylated exon 10-tau isoforms in corticobasal degeneration and progressive supranuclear palsy. Thus, neurofibrillary degeneration phenotypes are likely to be related to the phosphorylation of different combinations of tau isoforms (with and/or without exon 10-encoding sequence) in subpopulations of neurons.

Mackenzie, I. R. and D. G. Munoz (1998). "Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging." Neurology 50(4): 986-90.
Anti-inflammatory drugs have been suggested as a possible treatment for Alzheimer's disease (AD). The association of immune proteins and immune-competent microglial cells with senile plaques (SP) in both AD and normal aging suggests that these drugs may be able to modify the course of AD, either by interfering with SP formation or by suppressing the inflammation associated with SP. We compared postmortem brain tissue from elderly, nondemented, arthritic patients with a history of chronic nonsteroidal anti-inflammatory drug (NSAID) use (n = 32, aged 77 +/- 7 years) and nondemented control subjects with no history of arthritis or other condition that might promote the regular use of NSAIDs (n = 34, aged 77 +/- 6 years). In both the NSAID-treated group and control subjects, 59% of patients had some SP. There was no difference between the two groups in the mean number of plaques or in the number of specific SP subtypes (diffuse or neuritic). The degree of neurofibrillary pathology was also similar. Activated microglia were identified using CR3/43, an anti-MHC class II antibody. Both patient age and the presence of SP correlated positively with the number of CR3/43+ microglia (p < 0.02), whereas NSAID use was associated with less microglial activation (p < 0.01). Control patients with SP had almost three times the number of activated microglia as NSAID-treated patients with SP (11 versus 4 cells/mm2, p < 0.02). These results suggest that if NSAID use is effective in treating AD, the mechanism is more likely to be through the suppression of microglial activity than by inhibiting the formation of SP or neurofibrillary tangles.

Lippa, C. F., H. Fujiwara, et al. (1998). "Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes." Am J Pathol 153(5): 1365-70.
Missense mutations in the alpha-synuclein gene cause familial Parkinson's disease (PD), and alpha-synuclein is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease (AD). To determine whether alpha-synuclein is a component of LBs in familial AD (FAD) patients with known mutations in presenilin (n = 65) or amyloid precursor protein (n = 9) genes, studies were conducted with antibodies to alpha-, beta-, and gamma-synuclein. LBs were detected with alpha- but not beta- or gamma-synuclein antibodies in 22% of FAD brains, and alpha-synuclein-positive LBs were most numerous in amygdala where some LBs co-localized with tau-positive neurofibrillary tangles. As 12 (63%) of 19 FAD amygdala samples contained alpha-synuclein-positive LBs, these inclusions may be more common in FAD brains than previously reported. Furthermore, alpha-synuclein antibodies decorated LB filaments by immunoelectron microscopy, and Western blots revealed that the solubility of alpha-synuclein was reduced compared with control brains. The presence of alpha-synuclein-positive LBs was not associated with any specific FAD mutation. These studies suggest that insoluble alpha-synuclein aggregates into filaments that form LBs in many FAD patients, and we speculate that these inclusions may compromise the function and/or viability of affected neurons in the FAD brain.

Lindboe, C. F. and H. B. Hansen (1998). "The frequency of Lewy bodies in a consecutive autopsy series." Clin Neuropathol 17(4): 204-9.
In a consecutive autopsy series comprising 284 subjects > or = 50 years, 22 cases (7.7%) revealed Lewy bodies (LBs) of whom 21 had LBs in substantia nigra and/or locus ceruleus and 9 (3.2%) in the cerebral cortex. Only one case had cortical LBs without concomitant inclusions in the brain stem. The mean age of subjects with LBs was significantly higher than in those without (78.0 vs. 72.3 years). Cortical LBs had not been demonstrated in routine HE stains in any case and their identification necessitated the use of staining for ubiquitin. Although great care was taken not to interpret globose neurofibrillary tangles (NFTs) as LBs, anti-tau staining revealed that many of the suspected LBs were in fact NFTs. Thus, we recommend to apply both anti-ubiquitin and anti-tau staining for the demonstration of cortical LBs. In this material 21 of the 22 cases with LBs (95.5%) also revealed Alzheimer type of pathology as compared with 187 of 262 cases without LBs (71.4%). This difference may be explained by the higher age of subjects with LBs. Altogether 96 of the 284 cases (33.8%) had cerebrovascular lesions. None of the 9 cases with cortical LBs were clinically demented, and our results do not support the assertion that Lewy body-associated dementias should outnumber those of vascular origins.

Lidstrom, A. M., N. Bogdanovic, et al. (1998). "Clusterin (apolipoprotein J) protein levels are increased in hippocampus and in frontal cortex in Alzheimer's disease." Exp Neurol 154(2): 511-21.
We studied the multifunctional protein clusterin (apolipoprotein J, SGP-2, SP-40,40) in brain tissue using quantitative Western blotting and immunohistochemistry. The material included postmortem brains from 19 patients with Alzheimer's disease (AD), 6 with vascular dementia (VAD), and 7 age-matched control subjects. Intense clusterin staining was found in the soma of both neuronal and astroglial cells. In addition, positive staining was found in a portion of senile plaques (SP) in AD brains. Quantitative analysis showed that clusterin levels were significantly increased in AD, both in frontal cortex (150% of the control value, P = 0.002) and in the hippocampus (179% of the control value, P < 0.001), while normal clusterin levels were found in cerebellum (104% of the control value). No significant changes were found in VAD. Within the AD group, there was a significant negative correlation between clusterin levels in hippocampus and severity of dementia (r = -0.40), while no such correlation was found in frontal cortex (r = 0.12). No significant correlations were found between clusterin levels and the number of SP or neurofibrillary tangles. No significant differences in clusterin levels were found in any brain region between AD patients possessing different numbers of the ApoE4 allele. The increased clusterin levels in AD brain, together with the absence of a correlation between SP counts and clusterin levels, and the finding that clusterin is only found in a smaller portion of SP do not suggest a link between clusterin and beta-amyloid dependence. Instead we hypothesize that the increase is part of a regional response in AD brain.

Liao, A., R. M. Nitsch, et al. (1998). "Genetic association of an alpha2-macroglobulin (Val1000lle) polymorphism and Alzheimer's disease." Hum Mol Genet 7(12): 1953-6.
alpha2-Macroglobulin (A2M) is a proteinase inhibitor found in association with senile plaques (SP) in Alzheimer's disease (AD). A2M has been implicated biochemically in binding and degradation of the amyloid beta (Abeta) protein which accumulates in SP. We studied the relationship between Alzheimer's disease and a common A2M polymorphism, Val1000 (GTC)/Ile1000 (ATC), which occurs near the thiolester active site of the molecule. In an initial exploratory data set (90 controls and 171 Alzheimer's disease) we noted an increased frequency of the G/G genotype from 0.07 to 0.12. We therefore tested the hypothesis that the G/G genotype is over-represented in Alzheimer's disease in an additional independent data set: a group of 359 controls and 566 Alzheimer's disease patients. In the hypothesis testing cohort, the G/G genotype increased from 0.07 in controls to 0.12 in Alzheimer's disease (P < 0.05, Fisher's exact test). The odds ratio for Alzheimer's disease associated with the G/G genotype was 1.77 (1.16-2.70, P < 0.01) and in combination with APOE4 was 9.68 (95% CI 3.91-24.0, P < 0.001). The presence of the G allele was associated with an increase in Abeta burden in a small series. The A2M receptor, A2M-r/LRP, is a multifunctional receptor whose ligands include apolipoprotein E and the amyloid precursor protein. These four proteins have each been genetically linked to Alzheimer's disease, suggesting that they may participate in a common disease pathway.

Li, F., E. Iseki, et al. (1998). "Regional quantitative analysis of tau-positive neurons in progressive supranuclear palsy: comparison with Alzheimer's disease." J Neurol Sci 159(1): 73-81.
In patients with progressive supranuclear palsy (PSP), various tau-positive abnormal structures are found in the cerebral cortex as well as in the subcortical nuclei. Similar tau-positive abnormalities are also identified in cortico-basal degeneration (CBD). It is therefore questionable as to whether PSP can be neuropathologically differentiated from CBD. It also remains nuclear whether neurofibrillary tangles (NFT) in the cerebral