Apolipoprotein E polymorphism‐dependent effects on cellular function

Abstract

AbstractBackgroundWe have used a combination of cell‐based and biophysical approaches to investigate mechanisms by which apolipoprotein E (APOE) isoforms induce either protective or Alzheimer’s Disease (AD)‐associated pathological features.MethodAPOE polymorphism‐driven phenotypic and functional changes were investigated in both primary human astrocytes and central nervous system (CNS) cell types generated from a set of APOE isogenic hiPSC lines (APOE KO, E2, E3, E4). Using fluorescently‐labeled APOE, the transport of E2, E3 and E4 isoforms were tracked in live cells and changes in organelle co‐localization was assessed. Lipoprotein particles were isolated from conditioned media to investigate APOE polymorphism‐specific alternations in the assembly and secretion of high‐density lipoprotein (HDL) particles.ResultWe have identified APOE polymorphism‐specific changes in subcellular localization of APOE that are correlated with changes in cellular function, as well as the function of APOE as a major transporter of lipids and cholesterol in the brain.ConclusionOur results provide mechanistic insight into structure:function relationship of APOE in the context of pathological and protective isoforms.