Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease
Zengjie Xia, Emily E. Prescott, Agnieszka Urbanek, Hollie Wareing, Marianne C. King, Anna Olerinyova, Helen Dakin, Tom Leah, Katy Barnes, Martyna M. Matuszyk, Eleni Dimou, Eric Hidari, Yu P. Zhang, Jeff Y. L. Lam, John S. H. Danial, Michael R. Strickland, Hong Jiang, Peter Thornton, Damian C. Crowther, Sohvi Ohtonen, Mireia Gómez‐Budia, Simon Bell, Laura Ferraiuolo, Heather Mortiboys, Adrian Higginbottom, Stephen B. Wharton, David M. Holtzman, Tarja Malm, Rohan T. Ranasinghe, David Klenerman, Suman De
Abstract
Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related functions of Aβ aggregates throughout the course of aggregation. 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 Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.