Immunity
Volume 47, Issue 3, 19 September 2017, Pages 566-581.e9
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Article
The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases

https://doi.org/10.1016/j.immuni.2017.08.008Get rights and content
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Highlights

  • Microglia associated with neuritic Aβ-plaques exhibit a neurodegenerative phenotype

  • Phagocytosis of apoptotic neurons suppresses homeostatic microglia

  • The TREM2-APOE pathway regulates neurodegenerative microglial phenotypic switch

  • Targeting APOE signaling restores homeostatic and tolerogenic microglia

Summary

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.

Keywords

Alzheimer’s disease
amyotrophic lateral sclerosis
APOE
microglia
multiple sclerosis
neurodegeneration
transcriptional regulation
TREM2

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These authors contributed equally

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