Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Immunology, GENE-EXPRESSION SIGNATURE, ALZHEIMERS-DISEASE, APOLIPOPROTEIN-E, MOUSE MODEL, CELLS, DEFICIENCY, MACROPHAGE, DEGENERATION, PROGRESSION, ACTIVATION, APOE, Alzheimer’s disease, TREM2, amyotrophic lateral sclerosis, microglia, multiple sclerosis, neurodegeneration, transcriptional regulation, Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Apolipoproteins E, Apoptosis, Cerebral Cortex, Cluster Analysis, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Female, Gene Expression Profiling, Gene Expression Regulation, Gene Targeting, Humans, Immune Tolerance, Membrane Glycoproteins, Mice, Mice, Knockout, Mice, Transgenic, Microglia, Monocytes, Neurodegenerative Diseases, Neurons, Phagocytosis, Phenotype, Plaque, Amyloid, Receptors, Immunologic, Signal Transduction, Superoxide Dismutase-1, Transcriptome, Transforming Growth Factor beta, 1107 Immunology, 3204 Immunology

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 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.