4592 total record number 282 records this year

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

Krasemann, S;Madore, C;Cialic, R;Baufeld, C;Calcagno, N;El Fatimy, R;Beckers, L;O'Loughlin, E;Xu, Y;Fanek, Z;Greco, DJ;Smith, ST;Tweet, G;Humulock, Z;Zrzavy, T;Conde-Sanroman, P;Gacias, M;Weng, Z;Chen, H;Tjon, E;Mazaheri, F;Hartmann, K;Madi, A;Ulrich, JD;

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 -amyloid (A)-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.