AD-linked R47H-<i>TREM2</i>mutation induces disease-enhancing microglial states via AKT hyperactivation
Faten A. Sayed, Lay Kodama, Li Fan, Gillian Carling, Joe C. Udeochu, David Le, Qingyun Li, Lu Zhou, Man Ying Wong, Rose Horowitz, Pearly Ye, Hansruedi Mathys, Minghui Wang, Xiang Niu, Linas Mažutis, Xueqiao Jiang, Xueting Wang, Fuying Gao, Matthew Brendel, Maria A. Telpoukhovskaia, Tara E. Tracy, Georgia Frost, Yungui Zhou, Yaqiao Li, Yue Qiu, Zuolin Cheng, Guoqiang Yu, John Hardy, Giovanni Coppola, Fei Wang, Michael DeTure, Bin Zhang, Lei Xie, John Q. Trajnowski, Virginia M.‐Y. Lee, Shiaoching Gong, Subhash C. Sinha, Dennis W. Dickson, Wenjie Luo, Li Gan
Abstract
with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures. Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils. In R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a microglial modulating strategy to treat AD.