Journal
IMMUNITY
Volume 47, Issue 3, Pages 566-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2017.08.008
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Funding
- NIH National Institute of Neurological Disorders and Stroke [1R01NS088137]
- NIH National Institute on Aging (NIH-NIA) [R01AG051812, R01AG054672]
- National Multiple Sclerosis Society [5092A1]
- Amyotrophic Lateral Sclerosis Association [2087]
- Nancy Davis Foundation Faculty Award
- Cure Alzheimer's Fund (APOE: Butovsky)
- Department of Defense [AL120029]
- Thome Foundation [2011D002865]
- NIH-NIA [R01AG043975, R01AG040092, RF1AG054199-01]
- European Research Council [321366-Amyloid]
- Deutsche Forschungsgemeinschaft (DFG) [EXC 1010 SyNergy]
- Cure Alzheimer's Fund
- MetLife Foundation Award
- DFG [SFB841, GRK1459, SFB877]
- Austrian Science Foundation [P27744-B27]
- National Multiple Sclerosis Society
- [P50AG05681]
- [P01-AG0399]
- Austrian Science Fund (FWF) [P27744] Funding Source: Austrian Science Fund (FWF)
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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 b-amyloid (Ab)-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.
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