TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.
Identifieur interne : 000753 ( Main/Corpus ); précédent : 000752; suivant : 000754TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.
Auteurs : Tyler K. Ulland ; Wilbur M. Song ; Stanley Ching-Cheng Huang ; Jason D. Ulrich ; Alexey Sergushichev ; Wandy L. Beatty ; Alexander A. Loboda ; Yingyue Zhou ; Nigel J. Cairns ; Amal Kambal ; Ekaterina Loginicheva ; Susan Gilfillan ; Marina Cella ; Herbert W. Virgin ; Emil R. Unanue ; Yaming Wang ; Maxim N. Artyomov ; David M. Holtzman ; Marco ColonnaSource :
- Cell [ 1097-4172 ] ; 2017.
English descriptors
- KwdEn :
- AMP-Activated Protein Kinases (metabolism), Alzheimer Disease (metabolism), Alzheimer Disease (pathology), Animals (MeSH), Autophagy (MeSH), Creatinine (analogs & derivatives), Creatinine (metabolism), Disease Models, Animal (MeSH), Energy Metabolism (MeSH), Humans (MeSH), Lectins, C-Type (metabolism), Macrophages (metabolism), Membrane Glycoproteins (genetics), Membrane Glycoproteins (metabolism), Mice (MeSH), Microglia (metabolism), Microglia (pathology), Neurites (metabolism), Plaque, Amyloid (metabolism), Receptors, Immunologic (genetics), Receptors, Immunologic (metabolism), TOR Serine-Threonine Kinases (metabolism).
- MESH :
- chemical , analogs & derivatives : Creatinine.
- chemical , genetics : Membrane Glycoproteins, Receptors, Immunologic.
- chemical , metabolism : AMP-Activated Protein Kinases, Creatinine, Lectins, C-Type, Membrane Glycoproteins, Receptors, Immunologic, TOR Serine-Threonine Kinases.
- metabolism : Alzheimer Disease, Macrophages, Microglia, Neurites, Plaque, Amyloid.
- pathology : Alzheimer Disease, Microglia.
- Animals, Autophagy, Disease Models, Animal, Energy Metabolism, Humans, Mice.
Abstract
Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-β pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.
DOI: 10.1016/j.cell.2017.07.023
PubMed: 28802038
PubMed Central: PMC5573224
Links to Exploration step
pubmed:28802038Le document en format XML
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<author><name sortKey="Kambal, Amal" sort="Kambal, Amal" uniqKey="Kambal A" first="Amal" last="Kambal">Amal Kambal</name>
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<author><name sortKey="Virgin, Herbert W" sort="Virgin, Herbert W" uniqKey="Virgin H" first="Herbert W" last="Virgin">Herbert W. Virgin</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.</title>
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<author><name sortKey="Beatty, Wandy L" sort="Beatty, Wandy L" uniqKey="Beatty W" first="Wandy L" last="Beatty">Wandy L. Beatty</name>
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</affiliation>
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<author><name sortKey="Loboda, Alexander A" sort="Loboda, Alexander A" uniqKey="Loboda A" first="Alexander A" last="Loboda">Alexander A. Loboda</name>
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</affiliation>
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</affiliation>
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</affiliation>
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<term>Alzheimer Disease (metabolism)</term>
<term>Alzheimer Disease (pathology)</term>
<term>Animals (MeSH)</term>
<term>Autophagy (MeSH)</term>
<term>Creatinine (analogs & derivatives)</term>
<term>Creatinine (metabolism)</term>
<term>Disease Models, Animal (MeSH)</term>
<term>Energy Metabolism (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Lectins, C-Type (metabolism)</term>
<term>Macrophages (metabolism)</term>
<term>Membrane Glycoproteins (genetics)</term>
<term>Membrane Glycoproteins (metabolism)</term>
<term>Mice (MeSH)</term>
<term>Microglia (metabolism)</term>
<term>Microglia (pathology)</term>
<term>Neurites (metabolism)</term>
<term>Plaque, Amyloid (metabolism)</term>
<term>Receptors, Immunologic (genetics)</term>
<term>Receptors, Immunologic (metabolism)</term>
<term>TOR Serine-Threonine Kinases (metabolism)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Creatinine</term>
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<term>Receptors, Immunologic</term>
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<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>AMP-Activated Protein Kinases</term>
<term>Creatinine</term>
<term>Lectins, C-Type</term>
<term>Membrane Glycoproteins</term>
<term>Receptors, Immunologic</term>
<term>TOR Serine-Threonine Kinases</term>
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<term>Microglia</term>
<term>Neurites</term>
<term>Plaque, Amyloid</term>
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<term>Microglia</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Autophagy</term>
<term>Disease Models, Animal</term>
<term>Energy Metabolism</term>
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<front><div type="abstract" xml:lang="en">Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-β pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">28802038</PMID>
<DateCompleted><Year>2017</Year>
<Month>08</Month>
<Day>16</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>08</Month>
<Day>26</Day>
</DateRevised>
<Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1097-4172</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>170</Volume>
<Issue>4</Issue>
<PubDate><Year>2017</Year>
<Month>Aug</Month>
<Day>10</Day>
</PubDate>
</JournalIssue>
<Title>Cell</Title>
<ISOAbbreviation>Cell</ISOAbbreviation>
</Journal>
<ArticleTitle>TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.</ArticleTitle>
<Pagination><MedlinePgn>649-663.e13</MedlinePgn>
</Pagination>
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<ELocationID EIdType="doi" ValidYN="Y">10.1016/j.cell.2017.07.023</ELocationID>
<Abstract><AbstractText>Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-β pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.</AbstractText>
<CopyrightInformation>Copyright © 2017 Elsevier Inc. All rights reserved.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Ulland</LastName>
<ForeName>Tyler K</ForeName>
<Initials>TK</Initials>
<AffiliationInfo><Affiliation>Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Song</LastName>
<ForeName>Wilbur M</ForeName>
<Initials>WM</Initials>
<AffiliationInfo><Affiliation>Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Huang</LastName>
<ForeName>Stanley Ching-Cheng</ForeName>
<Initials>SC</Initials>
<AffiliationInfo><Affiliation>Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ulrich</LastName>
<ForeName>Jason D</ForeName>
<Initials>JD</Initials>
<AffiliationInfo><Affiliation>Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Sergushichev</LastName>
<ForeName>Alexey</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Computer Technologies Department, ITMO University, Saint Petersburg 197101, Russia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Beatty</LastName>
<ForeName>Wandy L</ForeName>
<Initials>WL</Initials>
<AffiliationInfo><Affiliation>Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Loboda</LastName>
<ForeName>Alexander A</ForeName>
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<AffiliationInfo><Affiliation>Computer Technologies Department, ITMO University, Saint Petersburg 197101, Russia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Zhou</LastName>
<ForeName>Yingyue</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Cairns</LastName>
<ForeName>Nigel J</ForeName>
<Initials>NJ</Initials>
<AffiliationInfo><Affiliation>Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kambal</LastName>
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