A variety of genetic and biochemical evidence suggests that amyloid ␤ (A␤) oligomers promote downstream errors in Tau action, in turn inducing neuronal dysfunction and cell death in Alzheimer and related dementias. To better understand molecular mechanisms involved in A␤-mediated neuronal cell death, we have treated primary rat hippocampal cultures with A␤ oligomers and examined the resulting cellular changes occurring before and during the induction of cell death with a focus on altered Tau biochemistry. The most rapid neuronal responses upon A␤ administration are activation of caspase 3/7 and calpain proteases. A␤ also appears to reduce Akt and Erk1/2 kinase activities while increasing GSK3␤ and Cdk5 activities. Shortly thereafter, substantial Tau degradation begins, generating relatively stable Tau fragments. Only a very small fraction of fulllength Tau remains intact after 4 h of A␤ treatment. In conflict with expectations based on suggested increases of GSK3␤ and Cdk5 activities, A␤ does not cause any major increases in phosphorylation of full-length Tau as assayed by immunoblotting one-dimensional gels with 11 independent site-and phosphospecific anti-Tau antibodies as well as by immunoblotting twodimensional gels probed with a pan-Tau antibody. There are, however, subtle and transient increases in Tau phosphorylation at 3-4 specific sites before its degradation. Taken together, these data are consistent with the notion that A␤-mediated neuronal cell death involves the loss of full-length Tau and/or the generation of toxic fragments but does not involve or require hyperphosphorylation of full-length Tau.Many neurodegenerative diseases are characterized by the accumulation of aggregated proteins in the brain. For example, the microtubule-associated protein Tau forms aggregates in a variety of neurodegenerative diseases known as tauopathies, including Alzheimer, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, and related dementias (1, 2). Alzheimer disease is distinguished from many other tauopathies by accumulation of a second pathological feature known as amyloid ␤ (A␤) 3 plaques (3, 4). Complementary genetic evidence demonstrates that errors in the action or regulation of either Tau or the amyloid precursor protein (which is proteolytically cleaved to produce A␤) can cause neuronal cell death and dementia in humans (5). Furthermore, experiments in both cultured rodent hippocampal neurons and transgenic mice demonstrate that A␤-mediated neuronal cell death and memory deficits require Tau (6, 7). Taken together, the data suggest an intrinsic relationship between A␤ and Tau dysfunction. Indeed, the widely cited "amyloid cascade hypothesis" proposes that A␤ oligomers induce aberrant effects on Tau, which in turn promotes neurodegeneration and dementia (8 -10).One central feature of Alzheimer and related dementias is that Tau isolated from affected brains is hyperphosphorylated (11,12). This observation led investigators to ...