Unbiased Metabolomic Investigation of Alzheimer’s Disease Brain Points to Dysregulation of Mitochondrial Aspartate Metabolism
Alzheimer’s disease (AD) is the most common cause of adult dementia. Yet the complete set of molecular changes accompanying this inexorable, neurodegenerative disease remains elusive. Here we adopted an unbiased lipidomics and metabolomics approach to surveying frozen frontal cortex samples from cli...
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| Veröffentlicht in: | Journal of proteome research 2016-02, Vol.15 (2), p.608-618 |
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| container_title | Journal of proteome research |
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| creator | Paglia, Giuseppe Stocchero, Matteo Cacciatore, Stefano Lai, Steven Angel, Peggi Alam, Mohammad Tauqeer Keller, Markus Ralser, Markus Astarita, Giuseppe |
| description | Alzheimer’s disease (AD) is the most common cause of adult dementia. Yet the complete set of molecular changes accompanying this inexorable, neurodegenerative disease remains elusive. Here we adopted an unbiased lipidomics and metabolomics approach to surveying frozen frontal cortex samples from clinically characterized AD patients (n = 21) and age-matched controls (n = 19), revealing marked molecular differences between them. Then, by means of metabolomic pathway analysis, we incorporated the novel molecular information into the known biochemical pathways and compared it with the results of a metabolomics meta-analysis of previously published AD research. We found six metabolic pathways of the central metabolism as well as glycerophospholipid metabolism predominantly altered in AD brains. Using targeted metabolomics approaches and MS imaging, we confirmed a marked dysregulation of mitochondrial aspartate metabolism. The altered metabolic pathways were further integrated with clinical data, showing various degrees of correlation with parameters of dementia and AD pathology. Our study highlights specific, altered biochemical pathways in the brains of individuals with AD compared with those of control subjects, emphasizing dysregulation of mitochondrial aspartate metabolism and supporting future venues of investigation. |
| doi_str_mv | 10.1021/acs.jproteome.5b01020 |
| format | Article |
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Yet the complete set of molecular changes accompanying this inexorable, neurodegenerative disease remains elusive. Here we adopted an unbiased lipidomics and metabolomics approach to surveying frozen frontal cortex samples from clinically characterized AD patients (n = 21) and age-matched controls (n = 19), revealing marked molecular differences between them. Then, by means of metabolomic pathway analysis, we incorporated the novel molecular information into the known biochemical pathways and compared it with the results of a metabolomics meta-analysis of previously published AD research. We found six metabolic pathways of the central metabolism as well as glycerophospholipid metabolism predominantly altered in AD brains. Using targeted metabolomics approaches and MS imaging, we confirmed a marked dysregulation of mitochondrial aspartate metabolism. The altered metabolic pathways were further integrated with clinical data, showing various degrees of correlation with parameters of dementia and AD pathology. Our study highlights specific, altered biochemical pathways in the brains of individuals with AD compared with those of control subjects, emphasizing dysregulation of mitochondrial aspartate metabolism and supporting future venues of investigation.</description><identifier>ISSN: 1535-3893</identifier><identifier>ISSN: 1535-3907</identifier><identifier>EISSN: 1535-3907</identifier><identifier>DOI: 10.1021/acs.jproteome.5b01020</identifier><identifier>PMID: 26717242</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>adults ; Aged ; Aged, 80 and over ; Alzheimer disease ; Alzheimer Disease - metabolism ; aspartic acid ; Autopsy ; biochemical pathways ; Brain - metabolism ; Female ; frontal lobe ; Humans ; image analysis ; Male ; meta-analysis ; Metabolic Networks and Pathways ; metabolism ; Metabolome ; metabolomics ; Metabolomics - methods ; mitochondria ; Mitochondria - metabolism ; neurodegenerative diseases ; patients ; Postmortem Changes ; proteome ; Spectrometry, Mass, Electrospray Ionization ; surveys</subject><ispartof>Journal of proteome research, 2016-02, Vol.15 (2), p.608-618</ispartof><rights>Copyright © 2015 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a552t-8d4d5e7a59968fd99830b9301ba24d5150c5a74e3784988266081de40f7b27e03</citedby><cites>FETCH-LOGICAL-a552t-8d4d5e7a59968fd99830b9301ba24d5150c5a74e3784988266081de40f7b27e03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jproteome.5b01020$$EPDF$$P50$$Gacs$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jproteome.5b01020$$EHTML$$P50$$Gacs$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26717242$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Paglia, Giuseppe</creatorcontrib><creatorcontrib>Stocchero, Matteo</creatorcontrib><creatorcontrib>Cacciatore, Stefano</creatorcontrib><creatorcontrib>Lai, Steven</creatorcontrib><creatorcontrib>Angel, Peggi</creatorcontrib><creatorcontrib>Alam, Mohammad Tauqeer</creatorcontrib><creatorcontrib>Keller, Markus</creatorcontrib><creatorcontrib>Ralser, Markus</creatorcontrib><creatorcontrib>Astarita, Giuseppe</creatorcontrib><title>Unbiased Metabolomic Investigation of Alzheimer’s Disease Brain Points to Dysregulation of Mitochondrial Aspartate Metabolism</title><title>Journal of proteome research</title><addtitle>J. Proteome Res</addtitle><description>Alzheimer’s disease (AD) is the most common cause of adult dementia. Yet the complete set of molecular changes accompanying this inexorable, neurodegenerative disease remains elusive. Here we adopted an unbiased lipidomics and metabolomics approach to surveying frozen frontal cortex samples from clinically characterized AD patients (n = 21) and age-matched controls (n = 19), revealing marked molecular differences between them. Then, by means of metabolomic pathway analysis, we incorporated the novel molecular information into the known biochemical pathways and compared it with the results of a metabolomics meta-analysis of previously published AD research. We found six metabolic pathways of the central metabolism as well as glycerophospholipid metabolism predominantly altered in AD brains. Using targeted metabolomics approaches and MS imaging, we confirmed a marked dysregulation of mitochondrial aspartate metabolism. The altered metabolic pathways were further integrated with clinical data, showing various degrees of correlation with parameters of dementia and AD pathology. Our study highlights specific, altered biochemical pathways in the brains of individuals with AD compared with those of control subjects, emphasizing dysregulation of mitochondrial aspartate metabolism and supporting future venues of investigation.</description><subject>adults</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Alzheimer disease</subject><subject>Alzheimer Disease - metabolism</subject><subject>aspartic acid</subject><subject>Autopsy</subject><subject>biochemical pathways</subject><subject>Brain - metabolism</subject><subject>Female</subject><subject>frontal lobe</subject><subject>Humans</subject><subject>image analysis</subject><subject>Male</subject><subject>meta-analysis</subject><subject>Metabolic Networks and Pathways</subject><subject>metabolism</subject><subject>Metabolome</subject><subject>metabolomics</subject><subject>Metabolomics - methods</subject><subject>mitochondria</subject><subject>Mitochondria - metabolism</subject><subject>neurodegenerative diseases</subject><subject>patients</subject><subject>Postmortem Changes</subject><subject>proteome</subject><subject>Spectrometry, Mass, Electrospray Ionization</subject><subject>surveys</subject><issn>1535-3893</issn><issn>1535-3907</issn><issn>1535-3907</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>N~.</sourceid><sourceid>EIF</sourceid><recordid>eNqFkctu1DAYhS0Eohd4BJCXbGbqSxzbG6ShpbRSK1jQteUkf2ZcJfZgO5XaDbwGr8eTYJiL2lVXtvyf79g-B6F3lMwpYfTEtml-u44hQxhhLhpSTskLdEgFFzOuiXy52yvND9BRSreEUCEJf40OWC2pZBU7RD9vfONsgg5fQ7ZNGMLoWnzp7yBlt7TZBY9DjxfDwwrcCPHPr98Jn7kEhcGfonUefwvO54RzwGf3KcJyGvbYtcuhXQXfRWcHvEhrG7PNsLvLpfENetXbIcHb7XqMbs4_fz-9mF19_XJ5uriaWSFYnqmu6gRIK7SuVd9prThpNCe0saxMqCCtsLICLlWllWJ1TRTtoCK9bJgEwo_Rx43vempG6FrwOdrBrKMbbbw3wTrzdOLdyizDnRFSUKVoMfiwNYjhx1TSMaNLLQyD9RCmZBipJdOcU_mslMqa6ZoIVhWp2EjbGFIJr9-_iBLzr2dTejb7ns2258K9f_ydPbUrtgjoRvCfD1P0Jd1nTP8C2dq8WQ</recordid><startdate>20160205</startdate><enddate>20160205</enddate><creator>Paglia, Giuseppe</creator><creator>Stocchero, Matteo</creator><creator>Cacciatore, Stefano</creator><creator>Lai, Steven</creator><creator>Angel, Peggi</creator><creator>Alam, Mohammad Tauqeer</creator><creator>Keller, Markus</creator><creator>Ralser, Markus</creator><creator>Astarita, Giuseppe</creator><general>American Chemical Society</general><scope>N~.</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20160205</creationdate><title>Unbiased Metabolomic Investigation of Alzheimer’s Disease Brain Points to Dysregulation of Mitochondrial Aspartate Metabolism</title><author>Paglia, Giuseppe ; Stocchero, Matteo ; Cacciatore, Stefano ; Lai, Steven ; Angel, Peggi ; Alam, Mohammad Tauqeer ; Keller, Markus ; Ralser, Markus ; Astarita, Giuseppe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a552t-8d4d5e7a59968fd99830b9301ba24d5150c5a74e3784988266081de40f7b27e03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>adults</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Alzheimer disease</topic><topic>Alzheimer Disease - metabolism</topic><topic>aspartic acid</topic><topic>Autopsy</topic><topic>biochemical pathways</topic><topic>Brain - metabolism</topic><topic>Female</topic><topic>frontal lobe</topic><topic>Humans</topic><topic>image analysis</topic><topic>Male</topic><topic>meta-analysis</topic><topic>Metabolic Networks and Pathways</topic><topic>metabolism</topic><topic>Metabolome</topic><topic>metabolomics</topic><topic>Metabolomics - methods</topic><topic>mitochondria</topic><topic>Mitochondria - metabolism</topic><topic>neurodegenerative diseases</topic><topic>patients</topic><topic>Postmortem Changes</topic><topic>proteome</topic><topic>Spectrometry, Mass, Electrospray Ionization</topic><topic>surveys</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Paglia, Giuseppe</creatorcontrib><creatorcontrib>Stocchero, Matteo</creatorcontrib><creatorcontrib>Cacciatore, Stefano</creatorcontrib><creatorcontrib>Lai, Steven</creatorcontrib><creatorcontrib>Angel, Peggi</creatorcontrib><creatorcontrib>Alam, Mohammad Tauqeer</creatorcontrib><creatorcontrib>Keller, Markus</creatorcontrib><creatorcontrib>Ralser, Markus</creatorcontrib><creatorcontrib>Astarita, Giuseppe</creatorcontrib><collection>American Chemical Society (ACS) Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of proteome research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Paglia, Giuseppe</au><au>Stocchero, Matteo</au><au>Cacciatore, Stefano</au><au>Lai, Steven</au><au>Angel, Peggi</au><au>Alam, Mohammad Tauqeer</au><au>Keller, Markus</au><au>Ralser, Markus</au><au>Astarita, Giuseppe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Unbiased Metabolomic Investigation of Alzheimer’s Disease Brain Points to Dysregulation of Mitochondrial Aspartate Metabolism</atitle><jtitle>Journal of proteome research</jtitle><addtitle>J. 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| subjects | adults Aged Aged, 80 and over Alzheimer disease Alzheimer Disease - metabolism aspartic acid Autopsy biochemical pathways Brain - metabolism Female frontal lobe Humans image analysis Male meta-analysis Metabolic Networks and Pathways metabolism Metabolome metabolomics Metabolomics - methods mitochondria Mitochondria - metabolism neurodegenerative diseases patients Postmortem Changes proteome Spectrometry, Mass, Electrospray Ionization surveys |
| title | Unbiased Metabolomic Investigation of Alzheimer’s Disease Brain Points to Dysregulation of Mitochondrial Aspartate Metabolism |
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