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Melatonin ameliorates cognitive deficits through improving mitophagy in a mouse model of Alzheimer’s disease
While melatonin is known to have protective effects in mitochondria‐related diseases, aging, and neurodegenerative disorders, there is poor understanding of the effects of melatonin treatment on mitophagy in Alzheimer's disease (AD). We used proteomic analysis to investigate the effects and und...
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Published in: | Journal of pineal research 2021-12, Vol.71 (4), p.e12774-n/a |
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creator | Chen, Chongyang Yang, Chao Wang, Jing Huang, Xi Yu, Haitao Li, Shangming Li, Shupeng Zhang, Zaijun Liu, Jianjun Yang, Xifei Liu, Gong‐Ping |
description | While melatonin is known to have protective effects in mitochondria‐related diseases, aging, and neurodegenerative disorders, there is poor understanding of the effects of melatonin treatment on mitophagy in Alzheimer's disease (AD). We used proteomic analysis to investigate the effects and underlying molecular mechanisms of oral melatonin treatment on mitophagy in the hippocampus of 4‐month‐old wild‐type mice versus age‐matched 5 × FAD mice, an animal model of AD. 5 × FAD mice showed disordered mitophagy and mitochondrial dysfunction as revealed by increased mtDNA, mitochondrial marker proteins and MDA production, decreased electron transport chain proteins and ATP levels, and co‐localization of Lamp1 and Tomm20. Melatonin treatment reversed the abnormal expression of proteins in the signaling pathway of lysosomes, pathologic phagocytosis of microglia, and mitochondrial energy metabolism. Moreover, melatonin restored mitophagy by improving mitophagosome–lysosome fusion via Mcoln1, and thus, ameliorated mitochondrial functions, attenuated Aβ pathology, and improved cognition. Concurrent treatment with chloroquine and melatonin blocked the positive behavioral and biochemical effects of administration with melatonin alone. Taken in concert, these results suggest that melatonin reduces AD‐related deficits in mitophagy such that the drug should be considered as a therapeutic candidate for the treatment of AD. |
doi_str_mv | 10.1111/jpi.12774 |
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We used proteomic analysis to investigate the effects and underlying molecular mechanisms of oral melatonin treatment on mitophagy in the hippocampus of 4‐month‐old wild‐type mice versus age‐matched 5 × FAD mice, an animal model of AD. 5 × FAD mice showed disordered mitophagy and mitochondrial dysfunction as revealed by increased mtDNA, mitochondrial marker proteins and MDA production, decreased electron transport chain proteins and ATP levels, and co‐localization of Lamp1 and Tomm20. Melatonin treatment reversed the abnormal expression of proteins in the signaling pathway of lysosomes, pathologic phagocytosis of microglia, and mitochondrial energy metabolism. Moreover, melatonin restored mitophagy by improving mitophagosome–lysosome fusion via Mcoln1, and thus, ameliorated mitochondrial functions, attenuated Aβ pathology, and improved cognition. Concurrent treatment with chloroquine and melatonin blocked the positive behavioral and biochemical effects of administration with melatonin alone. Taken in concert, these results suggest that melatonin reduces AD‐related deficits in mitophagy such that the drug should be considered as a therapeutic candidate for the treatment of AD.</description><identifier>ISSN: 0742-3098</identifier><identifier>EISSN: 1600-079X</identifier><identifier>DOI: 10.1111/jpi.12774</identifier><identifier>PMID: 34617321</identifier><language>eng</language><publisher>England</publisher><subject>Alzheimer Disease - drug therapy ; Alzheimer's disease ; Amyloid beta-Protein Precursor - genetics ; Animals ; Cognition ; melatonin ; Melatonin - pharmacology ; Mice ; mitochondrial function ; Mitophagy ; proteomic ; Proteomics</subject><ispartof>Journal of pineal research, 2021-12, Vol.71 (4), p.e12774-n/a</ispartof><rights>2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd</rights><rights>2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3254-6cf0a42ca4e5a4ef998132263d504faa4b36243f5ec9b740017010e52fc2e3e3</citedby><cites>FETCH-LOGICAL-c3254-6cf0a42ca4e5a4ef998132263d504faa4b36243f5ec9b740017010e52fc2e3e3</cites><orcidid>0000-0002-7807-374X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34617321$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Chongyang</creatorcontrib><creatorcontrib>Yang, Chao</creatorcontrib><creatorcontrib>Wang, Jing</creatorcontrib><creatorcontrib>Huang, Xi</creatorcontrib><creatorcontrib>Yu, Haitao</creatorcontrib><creatorcontrib>Li, Shangming</creatorcontrib><creatorcontrib>Li, Shupeng</creatorcontrib><creatorcontrib>Zhang, Zaijun</creatorcontrib><creatorcontrib>Liu, Jianjun</creatorcontrib><creatorcontrib>Yang, Xifei</creatorcontrib><creatorcontrib>Liu, Gong‐Ping</creatorcontrib><title>Melatonin ameliorates cognitive deficits through improving mitophagy in a mouse model of Alzheimer’s disease</title><title>Journal of pineal research</title><addtitle>J Pineal Res</addtitle><description>While melatonin is known to have protective effects in mitochondria‐related diseases, aging, and neurodegenerative disorders, there is poor understanding of the effects of melatonin treatment on mitophagy in Alzheimer's disease (AD). We used proteomic analysis to investigate the effects and underlying molecular mechanisms of oral melatonin treatment on mitophagy in the hippocampus of 4‐month‐old wild‐type mice versus age‐matched 5 × FAD mice, an animal model of AD. 5 × FAD mice showed disordered mitophagy and mitochondrial dysfunction as revealed by increased mtDNA, mitochondrial marker proteins and MDA production, decreased electron transport chain proteins and ATP levels, and co‐localization of Lamp1 and Tomm20. Melatonin treatment reversed the abnormal expression of proteins in the signaling pathway of lysosomes, pathologic phagocytosis of microglia, and mitochondrial energy metabolism. Moreover, melatonin restored mitophagy by improving mitophagosome–lysosome fusion via Mcoln1, and thus, ameliorated mitochondrial functions, attenuated Aβ pathology, and improved cognition. Concurrent treatment with chloroquine and melatonin blocked the positive behavioral and biochemical effects of administration with melatonin alone. Taken in concert, these results suggest that melatonin reduces AD‐related deficits in mitophagy such that the drug should be considered as a therapeutic candidate for the treatment of AD.</description><subject>Alzheimer Disease - drug therapy</subject><subject>Alzheimer's disease</subject><subject>Amyloid beta-Protein Precursor - genetics</subject><subject>Animals</subject><subject>Cognition</subject><subject>melatonin</subject><subject>Melatonin - pharmacology</subject><subject>Mice</subject><subject>mitochondrial function</subject><subject>Mitophagy</subject><subject>proteomic</subject><subject>Proteomics</subject><issn>0742-3098</issn><issn>1600-079X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp1kLtOwzAUhi0EoqUw8ALIK0Na33Ibq4pLUREMHdgi1zlOXSVxZKdFZeI1eD2ehJQAG0c651--8w8fQpeUjGk3k01jxpTFsThCQxoREpA4fTlGQxILFnCSJgN05v2GEJIkSXSKBlxENOaMDlH9CKVsbW1qLCsojXWyBY-VLWrTmh3gHLRRpvW4XTu7LdbYVI2zO1MXuDKtbday2OPDN67s1kN3cyix1Xhavq3BVOA-3z88zo0H6eEcnWhZerj4yRFa3t4sZ_fB4uluPpsuAsVZKIJIaSIFU1JA2K1O04RyxiKeh0RoKcWKR0xwHYJKV7EghMaEEgiZVgw48BG67muVs9470FnjTCXdPqMkOyjLOmXZt7KOverZZruqIP8jfx11wKQHXk0J-_-bsofneV_5BfwjeMw</recordid><startdate>202112</startdate><enddate>202112</enddate><creator>Chen, Chongyang</creator><creator>Yang, Chao</creator><creator>Wang, Jing</creator><creator>Huang, Xi</creator><creator>Yu, Haitao</creator><creator>Li, Shangming</creator><creator>Li, Shupeng</creator><creator>Zhang, Zaijun</creator><creator>Liu, Jianjun</creator><creator>Yang, Xifei</creator><creator>Liu, Gong‐Ping</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0002-7807-374X</orcidid></search><sort><creationdate>202112</creationdate><title>Melatonin ameliorates cognitive deficits through improving mitophagy in a mouse model of Alzheimer’s disease</title><author>Chen, Chongyang ; Yang, Chao ; Wang, Jing ; Huang, Xi ; Yu, Haitao ; Li, Shangming ; Li, Shupeng ; Zhang, Zaijun ; Liu, Jianjun ; Yang, Xifei ; Liu, Gong‐Ping</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3254-6cf0a42ca4e5a4ef998132263d504faa4b36243f5ec9b740017010e52fc2e3e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Alzheimer Disease - drug therapy</topic><topic>Alzheimer's disease</topic><topic>Amyloid beta-Protein Precursor - genetics</topic><topic>Animals</topic><topic>Cognition</topic><topic>melatonin</topic><topic>Melatonin - pharmacology</topic><topic>Mice</topic><topic>mitochondrial function</topic><topic>Mitophagy</topic><topic>proteomic</topic><topic>Proteomics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Chongyang</creatorcontrib><creatorcontrib>Yang, Chao</creatorcontrib><creatorcontrib>Wang, Jing</creatorcontrib><creatorcontrib>Huang, Xi</creatorcontrib><creatorcontrib>Yu, Haitao</creatorcontrib><creatorcontrib>Li, Shangming</creatorcontrib><creatorcontrib>Li, Shupeng</creatorcontrib><creatorcontrib>Zhang, Zaijun</creatorcontrib><creatorcontrib>Liu, Jianjun</creatorcontrib><creatorcontrib>Yang, Xifei</creatorcontrib><creatorcontrib>Liu, Gong‐Ping</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of pineal research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Chongyang</au><au>Yang, Chao</au><au>Wang, Jing</au><au>Huang, Xi</au><au>Yu, Haitao</au><au>Li, Shangming</au><au>Li, Shupeng</au><au>Zhang, Zaijun</au><au>Liu, Jianjun</au><au>Yang, Xifei</au><au>Liu, Gong‐Ping</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Melatonin ameliorates cognitive deficits through improving mitophagy in a mouse model of Alzheimer’s disease</atitle><jtitle>Journal of pineal research</jtitle><addtitle>J Pineal Res</addtitle><date>2021-12</date><risdate>2021</risdate><volume>71</volume><issue>4</issue><spage>e12774</spage><epage>n/a</epage><pages>e12774-n/a</pages><issn>0742-3098</issn><eissn>1600-079X</eissn><abstract>While melatonin is known to have protective effects in mitochondria‐related diseases, aging, and neurodegenerative disorders, there is poor understanding of the effects of melatonin treatment on mitophagy in Alzheimer's disease (AD). We used proteomic analysis to investigate the effects and underlying molecular mechanisms of oral melatonin treatment on mitophagy in the hippocampus of 4‐month‐old wild‐type mice versus age‐matched 5 × FAD mice, an animal model of AD. 5 × FAD mice showed disordered mitophagy and mitochondrial dysfunction as revealed by increased mtDNA, mitochondrial marker proteins and MDA production, decreased electron transport chain proteins and ATP levels, and co‐localization of Lamp1 and Tomm20. Melatonin treatment reversed the abnormal expression of proteins in the signaling pathway of lysosomes, pathologic phagocytosis of microglia, and mitochondrial energy metabolism. Moreover, melatonin restored mitophagy by improving mitophagosome–lysosome fusion via Mcoln1, and thus, ameliorated mitochondrial functions, attenuated Aβ pathology, and improved cognition. Concurrent treatment with chloroquine and melatonin blocked the positive behavioral and biochemical effects of administration with melatonin alone. Taken in concert, these results suggest that melatonin reduces AD‐related deficits in mitophagy such that the drug should be considered as a therapeutic candidate for the treatment of AD.</abstract><cop>England</cop><pmid>34617321</pmid><doi>10.1111/jpi.12774</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-7807-374X</orcidid></addata></record> |
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subjects | Alzheimer Disease - drug therapy Alzheimer's disease Amyloid beta-Protein Precursor - genetics Animals Cognition melatonin Melatonin - pharmacology Mice mitochondrial function Mitophagy proteomic Proteomics |
title | Melatonin ameliorates cognitive deficits through improving mitophagy in a mouse model of Alzheimer’s disease |
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