Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons

Human apolipoprotein (apo) E4, a major risk factor for Alzheimer's disease (AD), occurs in amyloid plaques and neurofibrillary tangles (NFTs) in AD br ains; however, its role in the pathogenesis of these lesions is unclear, He re we demonstrate that carboxyl-terminal-truncated forms of apoE, which occ ur in AD brains and cultured neurons, induce intracellular NFT-like inclusi ons in neurons. These cytosolic inclusions were composed of phosphorylated tau, phosphorylated neurofilaments of high molecular weight, and truncated apoE. Truncated apoE4, especially apoE4(Delta 272-299), induced inclusions in up to 75% of transfected neuronal cells, but not in transfected nonneuro nal cells. ApoE4 was more susceptible to truncation than apoE3 and resulted in much greater intracellular inclusion formation. These results suggest t hat apoE4 preferentially undergoes intracellular processing, creating a bio active fragment that interacts with cytoskeletal components and induces NFT -like inclusions containing phosphorylated tau and phosphorylated neurofila ments of high molecular weight in neurons.