Simulations and Experiments Reveal Diverse APOE States that Inform their Pathogenicity

Abstract

AbstractBackgroundMutations to the lipid transport protein Apolipoprotein E (APOE) can dramatically increase the risk of developing late‐onset Alzheimer’s Disease (AD) by up to 15‐fold, however a molecular description of why some isoforms are protective while others are pathological has remained elusive. We hypothesize that individual APOE isoforms sample distinct conformational landscapes that are modulated by the presence of lipids, and that these landscapes contain co‐existing pathological and protective states.MethodTo test this hypothesis, we carried out a combination of molecular dynamics (MD) simulations and single‐molecule FRET (smFRET) experiments to highlight the conformational heterogeneity of human APOE isoforms, thereby informing states that differentially traffic lipids into neurons.ResultOur data suggests that there is no single pathological or protective APOE conformation, but rather a broad spectrum of protective and susceptible conformations that impact disease and memory impairment.ConclusionBiophysical studies are powerful tools that can inform the molecular mechanisms driving Alzheimer’s Disease and help bridge the gap between genetic associations (e.g. APOE status) and clinical phenotypes such as amyloid buildup or memory impairment.