Association of phosphorylation site of tau protein with neuronal apoptosis in Alzheimer's disease

Abstract

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 ...

Ogt-Dependent X-Chromosome-Linked Protein Glycosylation Is a Requisite Modification in Somatic Cell Function and Embryo Viability

“…Interestingly, early mouse death and neuronal apoptosis have been previously associated with tau hyperphosphorylation (3,28). The early timing of postnatal death among mice bearing a neuronal Ogt ⌬ allele also reduced possibilities for additional studies of O-GlcNAc expression and function by this approach.…”

“…The tau protein was increased in total amount and found to be hyperphosphorylated. Previous studies have found a close association of hyperphosphorylated tau with neuronal apoptosis and early lethality in the mouse (3,28). Although no genetic linkage specifically to the Ogt allele has been made as yet in X-linked disease states among humans and mice, a rare neuralgic disorder classified as a form of Parkinson-dystonia has been mapped to the chromosomal region that includes the Ogt locus (41).…”

Binding of Tau to Heat Shock Protein 27 Leads to Decreased Concentration of Hyperphosphorylated Tau and Enhanced Cell Survival

“…Several studies have shown that hyperphosphorylated tau can cause apoptosis, and apoptotic cell death has been observed in postmortem AD brain and AD animal models (22)(23)(24). To examine whether pathological hyperphosphorylated tau causes apoptosis, activation of an effector caspase (caspase-3) was analyzed in a colorimetric assay.…”

P21 Gene Variation and Late-Onset Alzheimer’s Disease in the Italian Population

“…Previously, among other genes [11,12,13], we investigated P53 and P73 [14], two genes associated with the P53 protein [15], a sequence-specific transcription factor that regulates the expression of many genes involved in cell cycle arrest and apoptosis. Apoptosis of neuronal and glial cells is believed to be another important aspect of AD [16]. In the present study, we examined the P21 gene, which belongs to the same pathway as P53.…”