Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer's disease

Xia, Z.; Prescott, E.; Leah, T.; Dakin, H.; Dimou, E.; Zuo, Y.; Zhang, Y. P.; Lam, J. Y. L.; Danial, J. S. H.; Jiang, H.; Mortiboys, H. J.; Thornton, P.; Crowther, D. C.; Holtzman, D. M.; Ranasinghe, R. T.; Klenerman, D.; De, S.

doi:10.1101/2021.07.13.452239

bioRxiv · 10.1101/2021.07.13.452239

Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer's disease

Xia, Z.·Prescott, E.·Leah, T.·Dakin, H.·Dimou, E.·Zuo, Y.·Zhang, Y. P.·Lam, J. Y. L.·Danial, J. S. H.·Jiang, H.·Mortiboys, H. J.·Thornton, P.·Crowther, D. C.·Holtzman, D. M.·Ranasinghe, R. T.·Klenerman, D.·De, S.

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Abstract

Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimers Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-{beta} (A{beta}) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with A{beta} in the early stages of aggregation and then fall away as fibrillation happens. ApoE-A{beta} co-aggregates account for [~]50% of the mass of soluble A{beta} aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of A{beta}. Selectively removing non-lipidated apoE4-A{beta} co-aggregates enhances clearance of toxic A{beta} by glial cells, and reduces inflammation and membrane damage, demonstrating a clear path to AD therapeutics.

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Xia, Z., Prescott, E., Leah, T., Dakin, H., Dimou, E., Zuo, Y., Zhang, Y. P., Lam, J. Y. L., Danial, J. S. H., Jiang, H., Mortiboys, H. J., Thornton, P., Crowther, D. C., Holtzman, D. M., Ranasinghe, R. T., Klenerman, D., De, S.. 2021-07-14. Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer's disease. https://doi.org/10.1101/2021.07.13.452239

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