TY - JOUR
T1 - Identification of senescent, TREM2-expressing microglia in aging and Alzheimer’s disease model mouse brain
AU - Rachmian, Noa
AU - Medina, Sedi
AU - Cherqui, Ulysse
AU - Akiva, Hagay
AU - Deitch, Daniel
AU - Edilbi, Dunya
AU - Croese, Tommaso
AU - Salame, Tomer Meir
AU - Ramos, Javier Maria Peralta
AU - Cahalon, Liora
AU - Krizhanovsky, Valery
AU - Schwartz, Michal
PY - 2024/6
Y1 - 2024/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85190679892&partnerID=8YFLogxK
U2 - 10.1038/s41593-024-01620-8
DO - 10.1038/s41593-024-01620-8
M3 - Article
AN - SCOPUS:85190679892
SN - 1097-6256
VL - 27
SP - 1116
EP - 1124
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 6
ER -