Hyperleucinemia causes hippocampal retromer deficiency linking diabetes to Alzheimer's disease

NEUROBIOLOGY OF DISEASE

卷:65

Article

Morabito, Michael V.¹  Berman, Diego E.^2,3  Schneider, Remy T.²  Zhang, Yiying¹  Leibel, Rudolph L.¹  Small, Scott A.^2,4 

[1] Coll Phys & Surg, Dept Pediat, Div Mol Genet, Naomi Berrie Diabet Ctr, New York, NY 10032 USA

[2] Coll Phys & Surg, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA

[3] Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY USA

[4] Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA

关键词: Alzheimer's disease;    Obesity;    Diabetes;    Retromer;   

DOI  :  10.1016/j.nbd.2013.12.017

来源: Elsevier

【 摘 要 】

Type 2 diabetes (T2D) is a major risk factor for late-onset Alzheimer's disease (AD). A variety of metabolic changes related to T2D (e.g. hyperinsulinemia, hyperglycemia, and elevated branched-chain amino acids) have been proposed as mechanistic links, but the basis for this association remains unknown. Retromer-dependent trafficking is implicated in the pathogenesis of AD, and two key retromer proteins, VPS35 and VPS26, are deficient in the hippocampal formation of AD patients. We characterized VPS35 levels in five different mouse models of T2D/obesity to identify specific metabolic factors that could affect retromer levels in the brain. Mouse models in which hyperleucinemia was present displayed hippocampus-selective retromer deficiency. Wild-type lean mice fed a high leucine diet also developed hippocampal-selective retromer deficiency, and neuronal-like cells grown in high ambient leucine had reduced retromer complex proteins. Our results suggest that hyperleucinemia may account, in part, for the association of insulin resistance/T2D with AD. (C) 2014 Elsevier Inc. All rights reserved.

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