ArticleImmunity2017
The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases.
Registry-linked trialOpen access · bronzeAbstract read
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Article in Immunity, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06489548 (Assessment of Foralumab Safety and Modulation of Microglial Activation Evaluated by PET Imaging in Patients With Early Symptomatic Alzheimer's Disease), which is not on this map. Cited by 1,823 papers.
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1,823citing papers in PubMed
97.3field-weighted citation impact, top 1% of its field
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Assessment of Foralumab Safety and Modulation of Microglial Activation Evaluated by PET Imaging in Patients With Early Symptomatic Alzheimer's Disease
Who cites it
1,823 citing papers in PubMed, 2,923 citations in OpenAlex.
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1,763 more citing papers are in PubMed but not listed here.
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Authors and funding
38 authors at 12 institutions in 3 countries.
Susanne KrasemannAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Charlotte MadoreAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Ron CialicAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Caroline BaufeldAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Narghes CalcagnoAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Rachid El FatimyAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Lien BeckersAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Elaine O'LoughlinAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Yang XuDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
Zain FanekAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
David J GrecoAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Scott T SmithAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
George TweetAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Zachary HumulockAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Tobias ZrzavyCenter for Brain Research, Medical University of Vienna, Vienna, Austria.
Patricia Conde-SanromanDepartment of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA.
Mar GaciasDepartment of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA.
Zhiping WengDepartment of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
Hao ChenDepartment of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
Emily TjonAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Fargol MazaheriGerman Center for Neurodegenerative Diseases, Munich, Germany.
Kristin HartmannInstitute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Asaf MadiAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Jason D UlrichDepartment of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, USA.
Markus GlatzelInstitute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Anna WorthmannDepartment of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Joerg HeerenDepartment of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Bogdan BudnikMass Spectrometry and Proteomics Resource Laboratory, Faculty of Arts and Sciences Division of Science, Harvard University, Cambridge MA, USA.
Cynthia LemereAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Tsuneya IkezuDepartment of Pharmacology and Experimental Therapeutics and Department of Neurology, Boston University School of Medicine, MA, USA.
Frank L HeppnerDepartment of Neuropathology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Cluster of Excellence, NeuroCure, Charitéplatz 1, 10117 Berlin, Germany.
Vladimir LitvakDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
David M HoltzmanDepartment of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, USA.
Hans LassmannCenter for Brain Research, Medical University of Vienna, Vienna, Austria.
Howard L WeinerAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Jordi OchandoDepartment of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA.
Christian HaassGerman Center for Neurodegenerative Diseases, Munich, Germany; Biomedical Center, Biochemistry, Ludwig-Maximilians-Universität Munich, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.
Oleg ButovskyAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: obutovsky@rics.bwh.harvard.edu.
Harvard University · USBrigham and Women's Hospital · USUniversity of Massachusetts Chan Medical School · USIcahn School of Medicine at Mount Sinai · USHope Center for Neurological Disorders · USMedical University of Vienna · ATUniversität Hamburg · DEUniversity Medical Center Hamburg-Eppendorf · DEBoston University · USCharité - Universitätsmedizin Berlin · DEGerman Center for Neurodegenerative Diseases · DELudwig-Maximilians-Universität München · DE
Funding
Smartphone-Based "Burst" Cognitive AssessmentsP01AG003991 · NIA · WASHINGTON UNIVERSITY · PI Tammie Lee Smith Benzinger · 1985 to 2026
$69.5MWASHINGTON UNIVERSITY ALZHEIMERS DISEASE RESEARCH CENTERP50AG005681 · NIA · WASHINGTON UNIVERSITY · PI MORRIS, JOHN · 1985 to 2019
$52.1MRole of the Innate Immune System in Aging and Development of Alzheimer's DiseaseR01AG043975 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI WEINER, HOWARD L · 2012 to 2016
$8.3MExosome-mediated propagation of pathogenic tau proteinRF1AG054199 · NIA · MAYO CLINIC JACKSONVILLE · PI IKEZU, TSUNEYA · 2016 to 2021
$5.0MTargeting TGFb/IFNy-IRF8 Signaling to Modulate Monocytes and their Crosstalk with Microglia and Astrocytes to Treat Multiple SclerosisR01NS088137 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI Oleg Butovsky · 2014 to 2026
$4.9MTargeting the miR-155 and APOE-TREM2 pathways to restore dysfunctional microglia in Alzheimer’s diseaseR01AG054672 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI BUTOVSKY, OLEG, IKEZU, TSUNEYA · 2017 to 2021
$4.1MMicroglial mechanisms of postoperative CNS inflammation and cognitive declineR01AG051812 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI BUTOVSKY, OLEG, CROSBY, GREGORY · 2016 to 2020
$2.7MUnderstanding and Mitigating Vascular Side-Effects Associated with Anti-Amyloid ImmunotherapyR01NS136122 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI CYNTHIA A LEMERE · 2024 to 2026
$2.5MPyroglutamate Amyloid-beta as an Immunotherapeutic Target for Alzheimer's DiseaseR01AG040092 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI LEMERE, CYNTHIA A · 2012 to 2015
$1.5MLipid Nutrition and the BrainZ01AG000399 · NIA · NATIONAL INSTITUTE ON AGING · PI RAPOPORT, STANLEY I. · 2005 to 2008
$1.2MIntramural NIH HHS Z01 AG000399NIA NIH HHS P01 AG003991NIA NIH HHS P50 AG005681NIA NIH HHS R01 AG040092NIA NIH HHS R01 AG043975NIA NIH HHS R01 AG051812NIA NIH HHS R01 AG054672NIA NIH HHS RF1 AG054199NINDS NIH HHS R01 NS088137NINDS NIH HHS R01 NS136122
Abstract
Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.
Indexed as
Signal TransductionTranscriptomeAlzheimer DiseaseAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAnimalsApolipoproteins EApoptosisCerebral CortexCluster AnalysisDisease Models, AnimalEncephalomyelitis, Autoimmune, ExperimentalFemaleGene Expression ProfilingGene Expression RegulationGene TargetingAmyloid beta-PeptidesAmyloid beta-Protein PrecursorApolipoproteins EMembrane GlycoproteinsReceptors, ImmunologicSuperoxide Dismutase-1Transforming Growth Factor betaTrem2 protein, mouseAlzheimer’s diseaseamyotrophic lateral sclerosisAPOEmicrogliamultiple sclerosisneurodegenerationtranscriptional regulationTREM2
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Registered trials
NCT06489548ClinicalTrials.gov
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.