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

Rachmian, N.; Medina, S.; Cherqui, U.; Akiva, H.; Deitch, D.; Edilbi, D.; Croese, T.; Salame, T. M.; Peralta Ramos, J. M.; Cahalon, L.; Krizhanovsky, V.; Schwartz, M.

doi:10.1101/2023.03.20.533401

bioRxiv · 10.1101/2023.03.20.533401

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

Rachmian, N.·Medina, S.·Cherqui, U.·Akiva, H.·Deitch, D.·Edilbi, D.·Croese, T.·Salame, T. M.·Peralta Ramos, J. M.·Cahalon, L.·Krizhanovsky, V.·Schwartz, M.

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Abstract

Dementia in general, and Alzheimers disease (AD) in particular, are age-related diseases1,2. AD is associated with multiple causative factors3,4, among which local brain inflammation plays a significant role5. Microglia, the brain-resident immune cells6,7, are activated along the disease course7. 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 factor8,9. 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.

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Rachmian, N., Medina, S., Cherqui, U., Akiva, H., Deitch, D., Edilbi, D., Croese, T., Salame, T. M., Peralta Ramos, J. M., Cahalon, L., Krizhanovsky, V., Schwartz, M.. 2023-03-21. TREM2-dependent senescent microglia conserved in aging and Alzheimer's disease. https://doi.org/10.1101/2023.03.20.533401

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