Title

The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases

UMMS Affiliation

Department of Microbiology and Physiological Systems; Department of Biochemistry and Molecular Pharmacology; Program in Bioinformatics and Integrative Biology

Publication Date

9-19-2017

Document Type

Article

Disciplines

Biochemistry, Biophysics, and Structural Biology | Bioinformatics | Computational Biology | Immunology and Infectious Disease | Integrative Biology | Nervous System Diseases | Systems Biology

Abstract

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 beta-amyloid (Abeta)-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

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

DOI of Published Version

10.1016/j.immuni.2017.08.008

Source

Immunity. 2017 Sep 19;47(3):566-581.e9. doi: 10.1016/j.immuni.2017.08.008. Link to article on publisher's site

Journal/Book/Conference Title

Immunity

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

28930663

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