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Hyperleucinemia causes hippocampal retromer deficiency linking diabetes to Alzheimer's disease
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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235335/ https://www.ncbi.nlm.nih.gov/pubmed/24440570 http://dx.doi.org/10.1016/j.nbd.2013.12.017 |
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author | Morabito, Michael V. Berman, Diego E. Schneider, Remy T. Zhang, Yiying Leibel, Rudolph L. Small, Scott A. |
author_facet | Morabito, Michael V. Berman, Diego E. Schneider, Remy T. Zhang, Yiying Leibel, Rudolph L. Small, Scott A. |
author_sort | Morabito, Michael V. |
collection | PubMed |
description | 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 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. |
format | Online Article Text |
id | pubmed-4235335 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-42353352014-11-18 Hyperleucinemia causes hippocampal retromer deficiency linking diabetes to Alzheimer's disease Morabito, Michael V. Berman, Diego E. Schneider, Remy T. Zhang, Yiying Leibel, Rudolph L. Small, Scott A. Neurobiol Dis Article 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 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. 2014-01-14 2014-05 /pmc/articles/PMC4235335/ /pubmed/24440570 http://dx.doi.org/10.1016/j.nbd.2013.12.017 Text en © 2014 The Authors. Published by Elsevier Inc. All rights reserved. http://creativecommons.org/licenses/by-nc/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Article Morabito, Michael V. Berman, Diego E. Schneider, Remy T. Zhang, Yiying Leibel, Rudolph L. Small, Scott A. Hyperleucinemia causes hippocampal retromer deficiency linking diabetes to Alzheimer's disease |
title | Hyperleucinemia causes hippocampal retromer deficiency linking diabetes to Alzheimer's disease |
title_full | Hyperleucinemia causes hippocampal retromer deficiency linking diabetes to Alzheimer's disease |
title_fullStr | Hyperleucinemia causes hippocampal retromer deficiency linking diabetes to Alzheimer's disease |
title_full_unstemmed | Hyperleucinemia causes hippocampal retromer deficiency linking diabetes to Alzheimer's disease |
title_short | Hyperleucinemia causes hippocampal retromer deficiency linking diabetes to Alzheimer's disease |
title_sort | hyperleucinemia causes hippocampal retromer deficiency linking diabetes to alzheimer's disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235335/ https://www.ncbi.nlm.nih.gov/pubmed/24440570 http://dx.doi.org/10.1016/j.nbd.2013.12.017 |
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