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Altered APP Processing in Insulin-Resistant Conditions Is Mediated by Autophagosome Accumulation via the Inhibition of Mammalian Target of Rapamycin Pathway

Insulin resistance, one of the major components of type 2 diabetes mellitus (T2DM), is a known risk factor for Alzheimer’s disease (AD), which is characterized by an abnormal accumulation of intra- and extracellular amyloid β peptide (Aβ). Insulin resistance is known to increase Aβ generation, but t...

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Autores principales: Son, Sung Min, Song, Hyundong, Byun, Jayoung, Park, Kyong Soo, Jang, Hak Chul, Park, Young Joo, Mook-Jung, Inhee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501871/
https://www.ncbi.nlm.nih.gov/pubmed/22829447
http://dx.doi.org/10.2337/db11-1735
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author Son, Sung Min
Song, Hyundong
Byun, Jayoung
Park, Kyong Soo
Jang, Hak Chul
Park, Young Joo
Mook-Jung, Inhee
author_facet Son, Sung Min
Song, Hyundong
Byun, Jayoung
Park, Kyong Soo
Jang, Hak Chul
Park, Young Joo
Mook-Jung, Inhee
author_sort Son, Sung Min
collection PubMed
description Insulin resistance, one of the major components of type 2 diabetes mellitus (T2DM), is a known risk factor for Alzheimer’s disease (AD), which is characterized by an abnormal accumulation of intra- and extracellular amyloid β peptide (Aβ). Insulin resistance is known to increase Aβ generation, but the underlying mechanism that links insulin resistance to increased Aβ generation is unknown. In this study, we examined the effect of high-fat diet–induced insulin resistance on amyloid precursor protein (APP) processing in mouse brains. We found that the induced insulin resistance promoted Aβ generation in the brain via altered insulin signal transduction, increased β- and γ-secretase activities, and accumulation of autophagosomes. These findings were confirmed in diabetic db/db mice brains. Furthermore, in vitro experiments in insulin-resistant SH-SY5Y cells and primary cortical neurons confirmed the alteration of APP processing by insulin resistance–induced autophagosome accumulation. Defects in insulin signal transduction affect autophagic flux by inhibiting the mammalian target of rapamycin pathway, resulting in altered APP processing in these cell culture systems. Thus, the insulin resistance that underlies the pathogenesis of T2DM might also trigger accumulation of autophagosomes, leading to increased Aβ generation, which might be involved in the pathogenesis of AD.
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spelling pubmed-35018712013-12-01 Altered APP Processing in Insulin-Resistant Conditions Is Mediated by Autophagosome Accumulation via the Inhibition of Mammalian Target of Rapamycin Pathway Son, Sung Min Song, Hyundong Byun, Jayoung Park, Kyong Soo Jang, Hak Chul Park, Young Joo Mook-Jung, Inhee Diabetes Metabolism Insulin resistance, one of the major components of type 2 diabetes mellitus (T2DM), is a known risk factor for Alzheimer’s disease (AD), which is characterized by an abnormal accumulation of intra- and extracellular amyloid β peptide (Aβ). Insulin resistance is known to increase Aβ generation, but the underlying mechanism that links insulin resistance to increased Aβ generation is unknown. In this study, we examined the effect of high-fat diet–induced insulin resistance on amyloid precursor protein (APP) processing in mouse brains. We found that the induced insulin resistance promoted Aβ generation in the brain via altered insulin signal transduction, increased β- and γ-secretase activities, and accumulation of autophagosomes. These findings were confirmed in diabetic db/db mice brains. Furthermore, in vitro experiments in insulin-resistant SH-SY5Y cells and primary cortical neurons confirmed the alteration of APP processing by insulin resistance–induced autophagosome accumulation. Defects in insulin signal transduction affect autophagic flux by inhibiting the mammalian target of rapamycin pathway, resulting in altered APP processing in these cell culture systems. Thus, the insulin resistance that underlies the pathogenesis of T2DM might also trigger accumulation of autophagosomes, leading to increased Aβ generation, which might be involved in the pathogenesis of AD. American Diabetes Association 2012-12 2012-11-15 /pmc/articles/PMC3501871/ /pubmed/22829447 http://dx.doi.org/10.2337/db11-1735 Text en © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Metabolism
Son, Sung Min
Song, Hyundong
Byun, Jayoung
Park, Kyong Soo
Jang, Hak Chul
Park, Young Joo
Mook-Jung, Inhee
Altered APP Processing in Insulin-Resistant Conditions Is Mediated by Autophagosome Accumulation via the Inhibition of Mammalian Target of Rapamycin Pathway
title Altered APP Processing in Insulin-Resistant Conditions Is Mediated by Autophagosome Accumulation via the Inhibition of Mammalian Target of Rapamycin Pathway
title_full Altered APP Processing in Insulin-Resistant Conditions Is Mediated by Autophagosome Accumulation via the Inhibition of Mammalian Target of Rapamycin Pathway
title_fullStr Altered APP Processing in Insulin-Resistant Conditions Is Mediated by Autophagosome Accumulation via the Inhibition of Mammalian Target of Rapamycin Pathway
title_full_unstemmed Altered APP Processing in Insulin-Resistant Conditions Is Mediated by Autophagosome Accumulation via the Inhibition of Mammalian Target of Rapamycin Pathway
title_short Altered APP Processing in Insulin-Resistant Conditions Is Mediated by Autophagosome Accumulation via the Inhibition of Mammalian Target of Rapamycin Pathway
title_sort altered app processing in insulin-resistant conditions is mediated by autophagosome accumulation via the inhibition of mammalian target of rapamycin pathway
topic Metabolism
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501871/
https://www.ncbi.nlm.nih.gov/pubmed/22829447
http://dx.doi.org/10.2337/db11-1735
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