The relationships between astrocytic apoptosis and both senile plaques and neurofibrillary tangles (NFT) in gray matter lesions were examined quantitatively in Alzheimer's disease (AD) brains. Seven cortical regions were examined in seven AD brains by terminal dUTP nick end-labeling and immunolabeling with antibodies to glial fibrillary acidic protein, phosphorylated tau protein (AT180), apoptosis-related proteins (caspase-3, bcl-2, and CD95), and beta amyloid protein. Senile plaques showed the lowest density in the cornu ammonis. The density of apoptotic astrocytes was significantly correlated with the density of uncored and cored senile plaques. Neuronal caspase-3 and CD95 expression levels were too low to allow statistical assessment, but Bcl-2 was expressed strongly in the astrocytes and neurons with and without NFT. The correlation of the density of apoptotic astrocytes with apoptotic neurons and NFT was not statistically significant. The density of Bcl2-positive neurons correlated significantly with those of NFT and cored senile plaques, but Bcl2-positive astrocyte density showed no correlation with density of senile plaques or apoptotic astrocytes. These observations suggest that senile plaques may be a cause of astrocytic apoptosis in the gray matter, and that Bcl-2 protein is associated with NFT formation.

Objective –  The present study was performed to compare the distributions of three‐repeat (3R) and four‐repeat (4R) neurofibrillary tangles (NFT) with those of pretangles (p‐NFT), intracellular NFT (i‐NFT), and extracellular NFT (e‐NFT) in the hippocampus of Alzheimer's disease brains. Methods –  NFT labeling was performed using anti‐tau antibodies: pSer262 for p‐NFT, pSer422 for i‐NFT, AT8 for e‐NFT, RD3 for 3R, and RD4 for 4R tau, and Gallyas impregnation for the NFT population. RD4‐ and pSer422‐positive NFT were detected predominantly in sectors from CA2 to CA4, while RD3‐ and pSer262‐positive NFT were predominantly present in CA1, the entorhinal cortex, and the subiculum. The tau epitope recognized by pSer262 belongs to 4R tau but it showed a strong correlation with RD3‐ and AT8‐positive NFT. Conclusions –  Sectors CA2–CA4 showed predominantly 4R‐NFT containing the pSer422 epitope. pSer262 may detect the process of transformation from p‐NFT to i‐NFT, and e‐NFT consisted predominantly of 3R tau.

In addition to neuritic changes and amyloid deposits, neuronal and glial cell apoptosis is an important pathological feature of Alzheimer's disease (AD). Several factors have been postulated as causes or triggers of cellular apoptotic change. This study focused on a quantifiable relationship between phosphorylation sites of tau protein in the neurofibrillary tangles (NFT) and neuronal apoptosis. Five monoclonal anti-tau antibodies (AT180, AT8, HT7, Tau2 and Tau5) for NFT labeling and TdT-mediated UTP nick-end labeling (TUNEL) for localizing apoptotic change were employed. TUNEL-stained neuronal nuclei showed significantly high density in the entorhinal cortex, cornu ammonis (CA) and the parietal cortex. In all regions, density of TUNEL-stained neuronal nuclei showed significantly direct correlation with that of AT8-, AT180-and Tau2-positive neurons. Correlation of TUNEL-stained neuronal nuclei with tau-positive neurons differed depending on the cerebral regions. Density of TUNEL-stained neuronal nuclei showed inverse correlation with that of both AT8-positive and Gallyas-stained NFT in the CA and showed significantly direct correlation with AT8-and HT7-positive neurons in the frontal cortex. Density of tau-positive and Gallyas-stained NFT was higher than that of TUNEL-stained nuclei. We conclude that phosphorylation sites of tau, 159-163 and 202-205, are probably associated with neuronal apoptosis and apoptotic change follows abnormal phosphorylation of tau.2 Introduction Apoptosis, a programmed cell death by intrinsic mechanism to regulate cell population, has been shown to occur extensively in brains from patients with Alzheimer's disease (AD). In addition to neurofibrillary tangles (NFT) and beta amyloid protein (BAP) deposits, abundant apoptotic neuronal and glial cells are another pathological hallmark of AD [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Abnormal phosphorylation of the tau protein that leads to NFT formation, BAP deposits, high concentration of amyloid precursor protein (APP), caspase-3, the presenilin 1 and 2 gene and nitric oxide are considered to be important triggers of neuronal and glial apoptosis . Since NFT are present in the neuronal cytoplasm, NFT and neuronal apoptosis have been considered to be intimately associated with each other. To the best of our knowledge, 13 studies, ten in vivo [1, 3, 5, 7, 8-10, 13, 16, 18] and three in vitro [15,18,22], have addressed the relationship between NFT formation and neuronal apoptosis. However, it is still unclear whether neuronal apoptosis is a result or cause of abnormal phosphorylation of tau.Tau immunohistochemistry has differentiated pretangle neurons, known as stage 0 tangles [26][27], from argyrophilic NFT, and phosphorylation sites of the amino acid sequence of tau molecules have been analyzed in AD brains [28][29]. The pretangle neurons are believed to occur in the early stage and may disappear in the late stage of AD with some of them remaining unchanged. A recent study has demonstrated that neurons with ...

Neurofibrillary tangles (NFT) in Alzheimer’s disease (AD) are composed of abnormally phosphorylated tau proteins. Many phosphorylation sites have been reported in the AD brain, and NFT distribution was now roughly classified into 3 stages by Braak stage; this classification is based on pathological studies using the specific silver impregnation technique. The aim of our study was to examine the regional distribution of differently phosphorylated tau proteins with 5 site-specific monoclonal antibodies against the tau proteins, AT8, AT180, HT7, Tau2 and Tau5. We then compared our findings with those obtained from silver-stained NFT in an attempt to clarify the relationship between abnormal phosphorylation sites of the tau protein and NFT development. AT180 and AT8 labeled the highest and Tau2 the lowest density of NFT in any regions, while Tau5 and HT7 showed inconsistent distribution. In the limbic cortex, cornu ammonis, entorhinal cortex and cingulate cortex, silver-stained NFT density significantly correlated with density of NFT labeled with the 5 anti-tau antibodies, but cerebral isocortices showed heterogenous patterns of tau-positive NFT. Quantification of tau-positive regional NFT density showed that the AD-associated phosphorylation process progresses from the C-terminal to the N-terminal of the amino acid sequence, and correlation of Gallyas-stained NFT density with tau-labeled NFT density was more significant in the limbic cortices than the cerebral isocortices, which implies that stereotypical phosphorylation occurs in the limbic structures.

We report the second phenotype of frontotemporal dementia and parkinsonism linked to chromosome 17 with S305N similar to Pick’s disease pathology in two brothers. The brain of the older brother showed macroscopic atrophy compatible with Pick’s disease, and subsequent tau gene analysis revealed heterozygous S305N mutation in exon 10 of the tau gene. Round-shaped neuronal inclusions similar to Pick’s bodies were positive for phosphorylated serine 262 as well as other anti-tau antisera, which is different from immunoexpression of Pick’s bodies. Ultrastructurally, these neuronal inclusions consisted of straight, randomly orientated fibrils measuring approximately 10–20 nm in width and 60–600 nm in length. This ultrastructural profile is similar to that of the first case of S305N. S305N reported here can cause another phenotype closely resembling Pick’s disease.