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Defect of branched-chain amino acid metabolism promotes the development of Alzheimer’s disease by targeting the mTOR signaling
Diabetes is a risk factor for Alzheimer’s disease (AD) in humans. Branched-chain amino acids (BCAAs, namely valine, leucine, and isoleucine) metabolic defect is observed in human diabetes, which is associated with insulin resistance. But whether BCAAs connect diabetes and AD remains unknown. Here, w...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028749/ https://www.ncbi.nlm.nih.gov/pubmed/29802157 http://dx.doi.org/10.1042/BSR20180127 |
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author | Li, Huajie Ye, Dan Xie, Wei Hua, Fei Yang, Yilin Wu, Jian Gu, Aifang Ren, Yi Mao, Keshi |
author_facet | Li, Huajie Ye, Dan Xie, Wei Hua, Fei Yang, Yilin Wu, Jian Gu, Aifang Ren, Yi Mao, Keshi |
author_sort | Li, Huajie |
collection | PubMed |
description | Diabetes is a risk factor for Alzheimer’s disease (AD) in humans. Branched-chain amino acids (BCAAs, namely valine, leucine, and isoleucine) metabolic defect is observed in human diabetes, which is associated with insulin resistance. But whether BCAAs connect diabetes and AD remains unknown. Here, we show that BCAA metabolic defect may be one of the drivers of AD. BCAA levels were increased in the blood in human patients and mice with diabetes or AD. BCAA-enriched diet promoted the development of AD in mice as evidenced by the behavior and pathological analysis. Branched-chain amino acid transaminase 1 and 2 (BCAT1 and BCAT2) are the two enzymes for the first step metabolism of BCAAs by catalyzing BCAAs to generate branched-chain ketoacids. The expression of Bcat1 but not Bcat2 was significantly down-regulated in the brain tissues of diabetic, aged, and AD mice. Leucine up-regulated the phosphorylation of Tau but not affected the accumulation of amyloid β in the brain tissues or isolated neurons. In addition, knockdown of the expression of Bcat1, which would result in the accumulation of BCAAs, led to the same phenotype as BCAAs supplement in neurons. Interestingly, leucine supplement or Bcat1 knockdown promoted the activation of the mTOR signaling in the brains of AD mice or neurons. Subsequently, mTOR was critically involved in leucine and Bcat1 knockdown-mediated phosphorylation of Tau. Taken together, our findings demonstrated that diabetes-related BCAA accumulation in the brain tissues led to the phosphorylation of Tau and, subsequently, the development of diabetes-related AD. |
format | Online Article Text |
id | pubmed-6028749 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-60287492018-07-17 Defect of branched-chain amino acid metabolism promotes the development of Alzheimer’s disease by targeting the mTOR signaling Li, Huajie Ye, Dan Xie, Wei Hua, Fei Yang, Yilin Wu, Jian Gu, Aifang Ren, Yi Mao, Keshi Biosci Rep Research Articles Diabetes is a risk factor for Alzheimer’s disease (AD) in humans. Branched-chain amino acids (BCAAs, namely valine, leucine, and isoleucine) metabolic defect is observed in human diabetes, which is associated with insulin resistance. But whether BCAAs connect diabetes and AD remains unknown. Here, we show that BCAA metabolic defect may be one of the drivers of AD. BCAA levels were increased in the blood in human patients and mice with diabetes or AD. BCAA-enriched diet promoted the development of AD in mice as evidenced by the behavior and pathological analysis. Branched-chain amino acid transaminase 1 and 2 (BCAT1 and BCAT2) are the two enzymes for the first step metabolism of BCAAs by catalyzing BCAAs to generate branched-chain ketoacids. The expression of Bcat1 but not Bcat2 was significantly down-regulated in the brain tissues of diabetic, aged, and AD mice. Leucine up-regulated the phosphorylation of Tau but not affected the accumulation of amyloid β in the brain tissues or isolated neurons. In addition, knockdown of the expression of Bcat1, which would result in the accumulation of BCAAs, led to the same phenotype as BCAAs supplement in neurons. Interestingly, leucine supplement or Bcat1 knockdown promoted the activation of the mTOR signaling in the brains of AD mice or neurons. Subsequently, mTOR was critically involved in leucine and Bcat1 knockdown-mediated phosphorylation of Tau. Taken together, our findings demonstrated that diabetes-related BCAA accumulation in the brain tissues led to the phosphorylation of Tau and, subsequently, the development of diabetes-related AD. Portland Press Ltd. 2018-07-03 /pmc/articles/PMC6028749/ /pubmed/29802157 http://dx.doi.org/10.1042/BSR20180127 Text en © 2018 The Author(s). http://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Articles Li, Huajie Ye, Dan Xie, Wei Hua, Fei Yang, Yilin Wu, Jian Gu, Aifang Ren, Yi Mao, Keshi Defect of branched-chain amino acid metabolism promotes the development of Alzheimer’s disease by targeting the mTOR signaling |
title | Defect of branched-chain amino acid metabolism promotes the development of Alzheimer’s disease by targeting the mTOR signaling |
title_full | Defect of branched-chain amino acid metabolism promotes the development of Alzheimer’s disease by targeting the mTOR signaling |
title_fullStr | Defect of branched-chain amino acid metabolism promotes the development of Alzheimer’s disease by targeting the mTOR signaling |
title_full_unstemmed | Defect of branched-chain amino acid metabolism promotes the development of Alzheimer’s disease by targeting the mTOR signaling |
title_short | Defect of branched-chain amino acid metabolism promotes the development of Alzheimer’s disease by targeting the mTOR signaling |
title_sort | defect of branched-chain amino acid metabolism promotes the development of alzheimer’s disease by targeting the mtor signaling |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028749/ https://www.ncbi.nlm.nih.gov/pubmed/29802157 http://dx.doi.org/10.1042/BSR20180127 |
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