Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes.

ABSTRACT: Diabetes and impaired brain insulin signaling are linked to the pathogenesis of Alzheimer's disease (AD). The association between diabetes and AD-associated amyloid pathology is stronger among carriers of the apolipoprotein E (APOE) ε4 gene allele, the strongest genetic risk factor for late-onset AD. Here we report that apoE4 impairs neuronal insulin signaling in human apoE-targeted replacement (TR) mice in an age-dependent manner. High-fat diet (HFD) accelerates these effects in apoE4-TR mice at middle age. In primary neurons, apoE4 interacts with insulin receptor and impairs its trafficking by trapping it in the endosomes, leading to impaired insulin signaling and insulin-stimulated mitochondrial respiration and glycolysis. In aging brains, the increased apoE4 aggregation and compromised

SUBMITTER: Zhao N 

PROVIDER: S-EPMC5621659 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature