The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases

By S. Krasemann, C. Madore, R. Cialic, Caroline Baufeld, Narghes Calcagno, Rachid El Fatimy, Lien Beckers, Elaine O’Loughlin, Yang Xu, Zain Fanek and 28 more. Immunity, 2017

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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.

Subfields: Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/1785de4a79cd2110e10fb8f2b479aef720550d2c

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Citations in the corpus

The Major Risk Factors for Alzheimer’s Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques (2019, background): “We demonstrate here, in agreement with previous findings (Keren-Shaul et al., 2017; Krasemann et al., 2017), that ARMs induce Apoe expression up to 27-fold, compared to homeostatic microglia.”
Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain (2019, background): “For example, Keren-Shaul and co-workers(12) (2017) identified a protective, phagocytic microglia subtype (“DAM”) with the potential to restrict neurodegeneration, and Krasemann and colleagues(11) (2017) identified a dysfunctional, neurodegenerative microglia phenotype (“MGnD”).”
Microglia states and nomenclature: A field at its crossroads (2022, positive): “58,59,85,121 How the TREM2 receptor drives the DAM transcriptional phenotype remains unclear, although the TREM2-ApoE signaling pathway is necessary for the switch from homeostatic to MGnD. 59 Further investigations are required to fully elucidate the role of TREM2.”
Role of neuroinflammation in neurodegeneration development (2023, background): “found that APOE can bind with the intracellular domain of TREM2 and switch microglia from a homeostatic phenotype to neurodegenerative phenotype in multiple neurodegenerative models including AD, indicating APOE-TREM2 pathway as a proinflammatory signaling.(182) Except microglia and astrocytes, APOE”
Hallmarks of neurodegenerative diseases. (2023, positive): “232,233,237 Indeed, both ApoE and TREM2 modify protein aggregation and neurodegeneration in preclinical models of NDDs. TREM2 function appears to be protective against A b -re- lated local toxicity, whereas later in the tauopathy phase of disease, its function may be detrimental.”