{Reference Type}: Journal Article
{Title}: Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer's disease.
{Author}: Xia Z;Prescott EE;Urbanek A;Wareing HE;King MC;Olerinyova A;Dakin H;Leah T;Barnes KA;Matuszyk MM;Dimou E;Hidari E;Zhang YP;Lam JYL;Danial JSH;Strickland MR;Jiang H;Thornton P;Crowther DC;Ohtonen S;Gómez-Budia M;Bell SM;Ferraiuolo L;Mortiboys H;Higginbottom A;Wharton SB;Holtzman DM;Malm T;Ranasinghe RT;Klenerman D;De S;
{Journal}: Nat Commun
{Volume}: 15
{Issue}: 1
{Year}: 2024 Jun 1
{Factor}: 17.694
{DOI}: 10.1038/s41467-024-49028-z
{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.