Although apolipoprotein (apo) E4 is present in amyloid plaques and neurofibrillary tangles, its pathogenic role in Alzheimer's disease (AD) is unclear. Neuronal expression of apoE4 or apoE4 fragments in transgenic mice increases tau phosphorylation. To identify the kinase responsible for the increase, we studied transgenic mice expressing human apoE3 or apoE4 in neurons under the control of the neuron-specific enolase promoter. Brain levels of phosphorylated tau (p-tau) and phosphorylated (active) extracellular signal-regulated kinase (pErk) increased with age in both groups but were considerably higher in the apoE4 mice. Other candidate kinases, including glycogen synthase kinase 3 and cyclin-dependent kinase-5 and its activators p25 and p35, were not significantly altered. The increases in p-Erk and p-tau were highest in the hippocampus, intermediate in the cortex, and lowest in the cerebellum. In the hippocampus, p-Erk and p-tau accumulated in the hilus and CA3 region of the dentate gyrus, where high levels of zinc are found along mossy fibers. In Neuro-2a cells stably expressing apoE3 or apoE4, treatment with ZnCl 2 generated 2-fold more p-Erk and 3-fold more p-tau in the apoE4-expressing cells. Phosphorylation of Erk and tau was reduced by preincubation with the Erk pathway inhibitor U0126. Thus, increased tau phosphorylation in apoE4 transgenic mice was associated with Erk activation and could be modified by zinc, suggesting that apoE4 and zinc act in concert to contribute to the pathogenesis of AD.Human apolipoprotein (apo) 1 E4 has been identified as a major risk factor for Alzheimer's disease (AD) (1, 2). It increases the occurrence and lowers the age of onset of AD and is associated with ϳ40 -65% of cases of sporadic and familial AD (1, 2). The neuropathological hallmarks of AD are neuritic amyloid plaques and neurofibrillary tangles (NFTs) in the brain (3-5). The plaques are extracellular deposits consisting primarily of amyloid-beta (A) peptides (3-5), the proteolytic products of the amyloid protein precursor. NFTs are primarily intracellular deposits composed largely of highly phosphorylated tau (p-tau), a microtubule-associated protein (4), as well as phosphorylated neurofilaments of high molecular weight (6, 7). Both plaques and NFTs contain apoE (8 -10), but the role of apoE in the pathogenesis of these lesions is unclear.Several hypotheses have been proposed to explain the association of apoE4 with AD (10 -14). They include modulation of the deposition and clearance of A peptides and the formation of plaques (15-21), impairment of the antioxidative defense system (22), dysregulation of neuronal signaling pathways (23), altered phosphorylation of tau and NFT formation (24 -29), depletion of cytosolic androgen receptor levels in the brain (30, 31), potentiation of A-induced lysosomal leakage and apoptosis in neuronal cells (32), and promotion of endosomal abnormalities linked to A overproduction (33-35). However, the mechanisms of these apoE4-mediated detrimental effects are largely unknown, ...