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

Abstract

The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), 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)–TREM2, 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 TREM2 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.

• Authors: Faten A Sayed, Lay Kodama, Li Fan, Gillian K Carling, Joe C Udeochu, David Le, Qingyun Li, Lu Zhou, Man Ying Wong, Rose Horowitz, Pearly Ye, Hansruedi Mathys, Minghui Wang, Xiang Niu, Linas Mazutis, Xueqiao Jiang, Xueting Wang, Fuying Gao, Matthew Brendel, Maria Telpoukhovskaia, Tara E Tracy, Georgia Frost, Yungui Zhou, Yaqiao Li, Yue Qiu, Zuolin Cheng, Guoqiang Yu, John Hardy, Giovanni Coppola, Fei Wang, Michael A DeTure, Bin Zhang, Lei Xie, John Q Trajnowski, Virginia M Y Lee, Shiaoching Gong, Subhash C Sinha, Dennis W Dickson, Wenjie Luo, Li Gan
• Journal: Science translational medicine (Sci Transl Med) Vol. 13 Issue 622 Pg. eabe3947 (12 2021) ISSN: 1946-6242 [Electronic] United States
• PMID: 34851693 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Glycoproteins
• Receptors, Immunologic
• TREM2 protein, human
• Trem2 protein, mouse
• Proto-Oncogene Proteins c-akt

Topics

• Alzheimer Disease (genetics, metabolism)
• Animals
• Brain (metabolism)
• Female
• Humans
• Membrane Glycoproteins (genetics, metabolism)
• Mice
• Microglia (metabolism)
• Mutation (genetics)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, Immunologic (metabolism)