Apolipoprotein-E transforms intracellular Amyloid-β oligomers to a more toxic state

Abstract

AbstractIt is poorly understood why ApoE variants are major genetic risk factors in Alzheimer’s disease (AD), which is associated with the aggregation of amyloid beta (Aβ). Here we directly image specific changes in small Aβ oligomers in rat brain cells that correlate with the cellular ApoE content. An inhibitor of Aβ-ApoE interaction suppresses this change and concomitantly reduces Aβ toxicity in a dose-dependent manner. Single-molecule techniques show changes both in the conformation and the stoichiometry of the oligomers. hiPSC-derived neural stem cells from Alzheimer’s patients also show similar changes. Interaction with ApoE therefore changes the oligomeric state, membrane affinity, and toxicity of Aβ oligomers, and can be directly read out in live cells. Our findings suggest a rapid and quantitative assay for AD drug discovery.One-sentence summaryApoE causes specific toxicogenic modifications of Aβ oligomers, and these changes can be directly imaged in live cells.