title: Accumulation of autophagosomes contributes to enhanced amyloidogenic APP processing under insulin-resistant conditions.
abstract: Alzheimer disease (AD) is sometimes referred to as type III diabetes because of the shared risk factors for the two disorders. Insulin resistance, one of the major components of type II diabetes mellitus (T2DM), is a known risk factor for AD. Insulin resistance increases amyloid-β peptide (Aβ) generation, but the exact mechanism underlying the linkage of insulin resistance to increased Aβ generation in the brain is unknown. In this study, we investigated the effect of insulin resistance on amyloid β (A4) precursor protein (APP) processing in mice fed a high-fat diet (HFD), and diabetic db/db mice. We found that insulin resistance promotes Aβ generation in the brain via altered insulin signal transduction, increased BACE1/β-secretase and γ-secretase activities, and accumulation of autophagosomes. Using an in vitro model of insulin resistance, we found that defects in insulin signal transduction affect autophagic flux by inhibiting the mechanistic target of rapamycin (MTOR) pathway. The insulin resistance-induced autophagosome accumulation resulted in alteration of APP processing through enrichment of secretase proteins in autophagosomes. We speculate that the insulin resistance that underlies the pathogenesis of T2DM might alter APP processing through autophagy activation, which might be involved in the pathogenesis of AD. Therefore, we propose that insulin resistance-induced autophagosome accumulation becomes a potential linker between AD and T2DM.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Son
authors.forename: Hyundong
authors.initials: H
authors.lastname: Song
authors.forename: Jayoung
authors.initials: J
authors.lastname: Byun
authors.forename: Kyong Soo
authors.initials: KS
authors.lastname: Park
authors.forename: Hak Chul
authors.initials: HC
authors.lastname: Jang
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Park
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D008954:Models, Biological; D010588:Phagosomes / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: D016229:Amyloid beta-Peptides