Hyperphosphorylated tau is the major protein subunit of neurofibrillary tangles in Alzheimer's disease (AD) and related tauopathies. It is not understood, however, why the neurofibrillary tangle-containing neurons seen in the AD brains do not die of apoptosis but rather degeneration even though they are constantly awash in a proapoptotic environment. Here, we show that cells overexpressing tau exhibit marked resistance to apoptosis induced by various apoptotic stimuli, which also causes correlated tau hyperphosphorylation and glycogen synthase kinase 3 (GSK-3) activation. GSK-3 overexpression did not potentiate apoptotic stimulus-induced cell apoptosis in the presence of high levels of tau. The resistance of neuronal cells bearing hyperphosphorylated tau to apoptosis was also evident by the inverse staining pattern of PHF-1-positive tau and activated caspase-3 or fragmented nuclei in cells and the brains of rats or tau-transgenic mice. Tau hyperphosphorylation was accompanied by decreases in -catenin phosphorylation and increases in nuclear translocation of -catenin. Reduced levels of -catenin antagonized the antiapoptotic effect of tau, whereas overexpressing -catenin conferred resistance to apoptosis. These results reveal an antiapoptotic function of tau hyperphosphorylation, which likely inhibits competitively phosphorylation of -catenin by GSK-3 and hence facilitates the function of -catenin. Our findings suggest that tau phosphorylation may lead the neurons to escape from an acute apoptotic death, implying the essence of neurodegeneration seen in the AD brains and related tauopathies.Alzheimer's disease ͉ tau hyperphosphorylation ͉ glycogen synthase kinase-3 C hronic neurodegeneration characterized by accumulation of hyperphosphorylated tau and formation of neurofibrillary tangles (NFTs) is a hallmark lesion in Alzheimer's disease (AD) and related tauopathies (1-4). Although the mechanism underlying neurodegeneration remains elusive, the idea that neurons undergo apoptosis in the course of neurodegeneration is supported by studies showing that AD-related toxic stimuli, such as -amyloid, cause cell death as manifested by up-regulation of apoptotic markers (5, 6). However, apoptosis accounts for only a minor proportion of neurons lost in AD brains (7); most NFT-bearing neurons undergo chronic degeneration (8-13) rather than apoptosis, even though they are constantly exposed to apoptotic stimuli, suggesting that mechanism(s) exist enabling neurons to escape apoptosis.Studies on postmortem AD brains have demonstrated that abnormally hyperphosphorylated tau is the major protein subunit of NFT (1-4), which suggests that hyperphosphorylation of tau may play a role in leading the neuronal cells to desert apoptosis. Tau is a microtubule-associated protein. The major function of tau is to promote microtubule assembly and maintain the stability of the microtubules. The roles of tau hyperphosphorylation and accumulation in the development of neurofibrillary degeneration seen in the AD brains (1-4) and related t...