AD-linked R47H- TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation

The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 ( ), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the...

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Published in:	Science translational medicine Vol. 13; no. 622; p. eabe3947
Main Authors:	Sayed, Faten A, Kodama, Lay, Fan, Li, Carling, Gillian K, Udeochu, Joe C, Le, David, Li, Qingyun, Zhou, Lu, Wong, Man Ying, Horowitz, Rose, Ye, Pearly, Mathys, Hansruedi, Wang, Minghui, Niu, Xiang, Mazutis, Linas, Jiang, Xueqiao, Wang, Xueting, Gao, Fuying, Brendel, Matthew, Telpoukhovskaia, Maria, Tracy, Tara E, Frost, Georgia, Zhou, Yungui, Li, Yaqiao, Qiu, Yue, Cheng, Zuolin, Yu, Guoqiang, Hardy, John, Coppola, Giovanni, Wang, Fei, DeTure, Michael A, Zhang, Bin, Xie, Lei, Trajnowski, John Q, Lee, Virginia M Y, Gong, Shiaoching, Sinha, Subhash C, Dickson, Dennis W, Luo, Wenjie, Gan, Li
Format:	Journal Article
Language:	English
Published:	United States 01-12-2021
Subjects:	Alzheimer Disease - genetics Alzheimer Disease - metabolism Animals Brain - metabolism Female Humans Membrane Glycoproteins - genetics Membrane Glycoproteins - metabolism Mice Microglia - metabolism Mutation - genetics Proto-Oncogene Proteins c-akt - metabolism Receptors, Immunologic - metabolism
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Summary:	The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 ( ), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)– , we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human 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.
ISSN:	1946-6242
DOI:	10.1126/scitranslmed.abe3947