|
| Status |
Public on Sep 19, 2017 |
| Title |
The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases III |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| 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.
MG550 custom-design Nanosting chips were used to identify disease-associated vs. homeostatic molecular microglia signature in microglia in different disease models and transgenic models.
|
| |
|
| Overall design |
Nanostring MG550 chip profile of FCRLS+ sorted microglia. Note: data show mRNA transcriptoms/100ng RNA
|
| |
|
| 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 |
|
| Submission date |
Jul 20, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Oleg Butovsky |
| E-mail(s) |
obutovsky@rics.bwh.harvard.edu
|
| Phone |
1-617-525-5313
|
| Organization name |
Brigham and Women's Hospital, Harvard Medical School
|
| Department |
Center of Neurologic Diseases
|
| Lab |
Dr. Oleg Butovsky
|
| Street address |
77 Avenue Louis Pasteur, Office 614
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL23813 |
NanoString nCounter Mouse Gene Expression Custom Chip MG550 |
|
| Samples (50)
|
|
| This SubSeries is part of SuperSeries: |
| GSE101689 |
The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases |
|
| Relations |
| BioProject |
PRJNA395209 |
Less...
More...