Identification of senescent, TREM2-expressing microglia in aging and Alzheimer’s disease model mouse brain

Noa Rachmian, Sedi Medina, Ulysse Cherqui, Hagay Akiva, Daniel Deitch, Dunya Edilbi, Tommaso Croese, Tomer Meir Salame, Javier Maria Peralta Ramos, Liora Cahalon, Valery Krizhanovsky, Michal Schwartz

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer’s disease (AD) and dementia in general are age-related diseases with multiple contributing factors, including brain inflammation. Microglia, and specifically those expressing the AD risk gene TREM2, are considered important players in AD, but their exact contribution to pathology remains unclear. In this study, using high-throughput mass cytometry in the 5×FAD mouse model of amyloidosis, we identified senescent microglia that express high levels of TREM2 but also exhibit a distinct signature from TREM2-dependent disease-associated microglia (DAM). This senescent microglial protein signature was found in various mouse models that show cognitive decline, including aging, amyloidosis and tauopathy. TREM2-null mice had fewer microglia with a senescent signature. Treating 5×FAD mice with the senolytic BCL2 family inhibitor ABT-737 reduced senescent microglia, but not the DAM population, and this was accompanied by improved cognition and reduced brain inflammation. Our results suggest a dual and opposite involvement of TREM2 in microglial states, which must be considered when contemplating TREM2 as a therapeutic target in AD.

Original languageEnglish
Pages (from-to)1116-1124
Number of pages9
JournalNature Neuroscience
Volume27
Issue number6
DOIs
StatePublished Online - 18 Apr 2024

All Science Journal Classification (ASJC) codes

  • General Neuroscience

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