TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy

TLDR

Alzheimer’s disease is the leading cause of dementia, lacks disease‑modifying therapies, and recent genetic studies implicate TREM2 variants, with loss of TREM2 previously linked to worsened amyloid‑β toxicity. The study seeks to clarify the molecular mechanisms driving neurodegeneration to guide therapeutic development. TREM2 deficiency reduces neuroinflammation and protects against brain atrophy in tauopathy, revealing dual roles for TREM2/microglia in amyloid versus tau pathology that must be considered for TREM2‑targeted therapies.

Abstract

Significance Alzheimer’s disease (AD) is the most common cause of dementia and is a major public health problem for which there is currently no disease-modifying treatment. There is an urgent need for greater understanding of the molecular mechanisms underlying neurodegeneration in patients to create better therapeutic options. Recently, genetic studies uncovered novel AD risk variants in the microglial receptor, triggering receptor expressed on myeloid cells 2 (TREM2). Previous studies suggested that loss of TREM2 function worsens amyloid-β (Aβ) plaque-related toxicity. In contrast, we observe TREM2 deficiency mitigates neuroinflammation and protects against brain atrophy in the context of tau pathology. These findings indicate dual roles for TREM2 and microglia in the context of amyloid versus tau pathology, which are important to consider for potential treatments targeting TREM2.