Details

Autor(en) / Beteiligte

• Zhao, Na
• Liu, Chia-Chen
• Van Ingelgom, Alexandra J.
• Martens, Yuka A.
• Linares, Cynthia
• Knight, Joshua A.
• Painter, Meghan M.
• Sullivan, Patrick M.
• Bu, Guojun

Titel

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

Ist Teil von

• Neuron (Cambridge, Mass.), 2017-09, Vol.96 (1), p.115-129.e5

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 endosomal function further exacerbate the inhibitory effects of apoE4 on insulin signaling and related functions. Together, our study provides novel mechanistic insights into the pathogenic mechanisms of apoE4 and insulin resistance in AD. •ApoE4 impairs cerebral insulin signaling in an age-dependent manner•Peripheral insulin resistance and apoE4 synergistically impair insulin signaling•ApoE4 reduces insulin-IR interaction and impairs IR trafficking•ApoE4 aggregation and endosomal dysfunction impair insulin signaling with aging Zhao et al. demonstrates that aging and peripheral insulin resistance induces impairment of cerebral insulin signaling in human apoE4-targeted replacement mice. ApoE4 interferes with insulin receptor signaling by blocking its interaction with insulin and trapping the receptor in the endosomes.