TREM2-dependent senescent microglia conserved in aging and Alzheimer’s disease

Abstract

Dementia in general, and Alzheimer's disease (AD) in particular, are age-related diseases (1,2). AD is associated with multiple causative factors (3,4), among which local brain inflammation plays a significant role (5). Microglia, the brain-resident immune cells, are activated along the disease course (6,7). Yet, their contribution to the disease progression is still controversial. Here, using high-throughput mass cytometry for microglial immuno-phenotyping, we identified accumulation of senescent microglia in several pathologies associated with cognitive decline. These senescent microglia have a unique profile conserved across the multiple conditions investigated, including aging, mouse models of amyloidosis, and tauopathy. Moreover, we found that the expression of markers of senescence correlates with levels of TREM2, whose polymorphism was identified by GWAS as an AD risk factor (8,9). A TREM2-null AD mouse model showed lower levels of senescent microglia, relative to TREM2-intact AD mice. Senolysis using the drug ABT-73710,11 in an AD mouse model reduced the abundance of TREM2-senescent microglia without affecting levels of TREM2-dependent activated microglia, ameliorated cognitive deficits, and reduced brain inflammation. These results reveal the unexpected contribution of TREM2 to accumulation of senescent microglia in AD pathology, an effect that must be considered when targeting TREM2 as a therapeutic approach.

Cellular senescence in brain aging and cognitive decline

“…TREM2 appears to facilitate the pro-inflammatory disease-associated microglia (DAM) phenotype that appears in various CNS disease states (Keren-Shaul et al, 2017). It was recently shown that TREM2-expressing senescent microglia accumulate in aged and AD mouse brains, which share significant transcriptomic overlap with 'highly activated microglia' , a subset that uniquely appears in the brains of aged mice and may trigger neuroinflammatory responses (Rachmian et al, 2023). Depleting TREM2-positive senescent microglia in 5xFAD mice (which are models of accelerated Aβ accumulation and AD) significantly improved cognitive status and decreased levels of inflammatory cytokines in the brain (Rachmian et al, 2023).…”