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.

APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). ApoE4 increases brain amyloid-β (Aβ) pathology relative to other ApoE isoforms1. However, whether APOE independently influences tau pathology, the other major proteinopathy of AD and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knockin (KI) or ApoE knockout (KO) background, we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by 3 months of age compared to P301S/E2, P301S/E3 and P301S/EKO mice. By 9 months of age, P301S mice with different ApoE genotypes display distinct p-tau staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity following LPS treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of TNFα secretion and markedly reduced neuronal viability compared to neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNFα. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared to the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In Aβ-pathology positive individuals with symptomatic AD who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independent of Aβ pathology. ApoE4 exerts a “toxic” gain of function whereas the absence of ApoE is protective.