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Status |
Public on Sep 19, 2017 |
Title |
The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases I |
Organism |
Mus musculus |
Experiment type |
Expression profiling by array
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Summary |
Microglia play a pivotal role in the maintenance of brain homeostasis, but lose their homeostatic function during the course of neurodegenerative disorders. We identified a specific APOE-dependent molecular signature in microglia isolated from mouse models of amyotrophic lateral sclerosis, multiple sclerosis and Alzheimer’s disease (SOD1, EAE and APP-PS1) and in microglia surrounding neuritic A-plaques in human Alzheimer’s disease brain. This is mediated by a switch from a (M0)-homeostatic to (MGnD)-neurodegenerative phenotype following phagocytosis of apoptotic neurons via the TREM2-APOE pathway. TREM2 induces APOE signaling which is a negative regulator of the transcription program in M0-homeostatic microglia. Targeting the TREM2-APOE pathway restores the M0-homeostatic signature of microglia in APP-PS1 and SOD1 mice and prevents from neuronal loss in an acute model of neurodegeneration. In SOD1 mice, TREM2 regulates MGnD in a gender-dependent manner. APOE-mediated MGnD microglia lose their tolerogenic function. Taken together, our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target to restore homeostatic microglia. MG468 custom-design Nanosting chips were used to identify disease-associated vs. homeostatic molecular microglia signature in microglia in different disease models and transgenic models.
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Overall design |
Nanostring MG468 chip profile of FCRLS+ microglia sorted from spinal cords of WT and SOD1 mice. Note: data show mRNA transcriptoms/100ng RNA
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Contributor(s) |
Butovsky O |
Citation(s) |
28930663 |
NIH grant(s) |
Grant ID |
Grant title |
Affiliation |
Name |
R01 AG051812 |
Microglial mechanisms of postoperative CNS inflammation and cognitive decline |
BRIGHAM AND WOMEN'S HOSPITAL |
Oleg Butovsky |
R01 NS088137 |
Mechanism of regulation of CNS inflammation by microglia |
BRIGHAM AND WOMEN'S HOSPITAL |
Oleg Butovsky |
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Submission date |
Jul 20, 2017 |
Last update date |
Jul 25, 2021 |
Contact name |
Oleg Butovsky |
E-mail(s) |
obutovsky@rics.bwh.harvard.edu
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Phone |
1-617-525-5313
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Organization name |
Brigham and Women's Hospital, Harvard Medical School
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Department |
Center of Neurologic Diseases
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Lab |
Dr. Oleg Butovsky
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Street address |
77 Avenue Louis Pasteur, Office 614
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City |
Boston |
State/province |
MA |
ZIP/Postal code |
02115 |
Country |
USA |
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Platforms (1) |
GPL23811 |
NanoString nCounter Mouse Gene Expression Custom Chip MG468 |
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Samples (63)
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This SubSeries is part of SuperSeries: |
GSE101689 |
The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases |
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Relations |
BioProject |
PRJNA395208 |