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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 IV |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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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.
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| Overall design |
Illumina NextSeq500 was used to identify disease-associated vs. homeostatic molecular microglia signature in microglia in different disease models and transgenic models.
Bulk microglia (1,000 cells/sample) FCRLS+ sorted microglia.
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| Contributor(s) |
Butovsky O |
| Citation(s) |
28930663 |
| Submission date |
Aug 11, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Oleg Butovsky |
| E-mail(s) |
obutovsky@rics.bwh.harvard.edu
|
| 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
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (20)
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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 |
PRJNA398040 |
| SRA |
SRP115307 |
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