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

Abstract

SUMMARY Microglia play a pivotal role in 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 human AD brains. The APOE pathway mediated a switch from a homeostatic to neurodegenerative microglia phenotype following phagocytosis of apoptotic neurons. Triggering receptor expressed on myeloid cells 2 (TREM2) 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 led to a loss in their tolerogenic function. Taken together, our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target to restore homeostatic microglia.

Pro‐inflammatory activation of microglia in the brain of patients with sepsis

“…The purinergic receptor P2RY12, sensing ADP release from damaged tissue and being necessary for rapid migration of cells to the site of tissue damage , is one of the key markers for the homeostatic phenotype of microglia. In line with this is the nearly complete loss of P2RY12 expression on microglia in active experimental and human inflammatory and neurodegenerative lesions . However, it has been shown that P2RY12 is lost in a major subpopulation of microglia in the normal human brain and it was a surprise that systemic immune activation in sepsis did not lead to a further downregulation of its expression in microglia.…”

“…The presence of TMEM119 reactivity in P2RY12 negative microglia suggests that loss of this purinergic receptor is not due to the recruitment of circulating myeloid cells, which differentiate into a microglia‐like morphological phenotype. We have shown previously that the loss of P2RY12 reactivity correlates with the extent of neurodegeneration in human cortex of controls and Alzheimer's disease patients . Thus, neurodegeneration instead of inflammation may be the key trigger for the downregulation of P2RY12 expression on CNS microglia.…”

Unique microglia recovery population revealed by single-cell RNAseq following neurodegeneration

“…Such kinetics of microgliosis are in sharp contrast to mouse models of chronic or severe neurodegeneration in which the resolution of microgliosis is not observed [21, 23, 30]. Notably, bulk RNAseq analysis revealed no change in gene regulation between the lesion and contralateral FN in at 60 d after FNX [43].…”

Microglial Phenotypes and Functions in Multiple Sclerosis

“…TREM2 expression by microglia is known to modulate the inflammatory response by suppression of microglia-mediated cytokine production and secretion, and by regulation of phagocytic pathways that clear neuronal debris (Hsieh et al 2009;Krasemann et al 2017). A recent study by Bogie et al identified a scavenger receptor, collectin placenta 1 (CL-P1), as a novel receptor in the uptake of myelin by microglia ( phagocytes).…”