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

Dey, A.; Verma, A.; Bhaskar, U.; Sarkar, B.; Kallianpur, M.; Visvakarma, V.; Das, A. K.; Garai, K.; Mukherjee, O.; Ishii, K.; Tahara, T.; Maiti, S.

doi:10.1101/2023.09.03.556061

bioRxiv · 10.1101/2023.09.03.556061

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

Dey, A.·Verma, A.·Bhaskar, U.·Sarkar, B.·Kallianpur, M.·Visvakarma, V.·Das, A. K.·Garai, K.·Mukherjee, O.·Ishii, K.·Tahara, T.·Maiti, S.

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Abstract

It is poorly understood why ApoE variants are major genetic risk factors in Alzheimers disease (AD), which is associated with the aggregation of amyloid beta (A{beta}). Here we directly image specific changes in small A{beta} oligomers in rat brain cells that correlate with the cellular ApoE content. An inhibitor of A{beta}-ApoE interaction suppresses this change and concomitantly reduces A{beta} 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 Alzheimers patients also show similar changes. Interaction with ApoE therefore changes the oligomeric state, membrane affinity, and toxicity of A{beta} 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 A{beta} oligomers, and these changes can be directly imaged in live cells.

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Dey, A., Verma, A., Bhaskar, U., Sarkar, B., Kallianpur, M., Visvakarma, V., Das, A. K., Garai, K., Mukherjee, O., Ishii, K., Tahara, T., Maiti, S.. 2023-09-03. Apolipoprotein-E transforms intracellular Amyloid-β oligomers to a more toxic state. https://doi.org/10.1101/2023.09.03.556061

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