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AD-linked R47H-TREM2 mutation induces disease-enhancing proinflammatory microglial states in mice and humans

Faten A. Sayed, View ORCID ProfileLay Kodama, View ORCID ProfileJoe C. Udeochu, Li Fan, View ORCID ProfileGillian K. Carling, David Le, View ORCID ProfileQingyun Li, Lu Zhou, Hansruedi Mathys, Minghui Wang, Xiang Niu, Linas Mazutis, Xueqiao Jiang, Xueting Wang, Man Ying Wong, Fuying Gao, Maria Telpoukhovskaia, Tara E. Tracy, Georgia Frost, Yungui Zhou, Yaqiao Li, Matthew Brendel, View ORCID ProfileYue Qiu, Zuolin Cheng, Guoqiang Yu, John Hardy, Giovanni Coppola, Shiaoching Gong, Fei Wang, Michael A. DeTure, Bin Zhang, Lei Xie, Dennis W. Dickson, Wenjie Luo, Li Gan
doi: https://doi.org/10.1101/2020.07.24.218719
Faten A. Sayed
1Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA
2Gladstone Institute of Neurological Disease, San Francisco, CA, USA
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Lay Kodama
1Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA
2Gladstone Institute of Neurological Disease, San Francisco, CA, USA
3Helen and Robert Appel Alzheimer’s Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
4Medical Scientist Training Program and Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA
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Joe C. Udeochu
3Helen and Robert Appel Alzheimer’s Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
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Li Fan
3Helen and Robert Appel Alzheimer’s Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
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Gillian K. Carling
3Helen and Robert Appel Alzheimer’s Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
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  • ORCID record for Gillian K. Carling
David Le
2Gladstone Institute of Neurological Disease, San Francisco, CA, USA
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Qingyun Li
5Department of Neurobiology, Stanford University School of Medicine, Stanford, CA, USA
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Lu Zhou
5Department of Neurobiology, Stanford University School of Medicine, Stanford, CA, USA
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Hansruedi Mathys
6The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
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Minghui Wang
7Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, NY, USA
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Xiang Niu
8Tri-Institutional Computational Biology & Medicine Program, Weill Cornell Medical College, NY, USA
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Linas Mazutis
9Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Xueqiao Jiang
6The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
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Xueting Wang
3Helen and Robert Appel Alzheimer’s Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
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Man Ying Wong
3Helen and Robert Appel Alzheimer’s Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
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Fuying Gao
10Departments of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
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Maria Telpoukhovskaia
2Gladstone Institute of Neurological Disease, San Francisco, CA, USA
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Tara E. Tracy
2Gladstone Institute of Neurological Disease, San Francisco, CA, USA
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Georgia Frost
11Chemical Biology Program, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA
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Yungui Zhou
2Gladstone Institute of Neurological Disease, San Francisco, CA, USA
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Yaqiao Li
2Gladstone Institute of Neurological Disease, San Francisco, CA, USA
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Matthew Brendel
12Institute for Computational Biomedicine, Dept. of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
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Yue Qiu
13Department of Computer Science, Hunter College, & The Graduate Center, The City University of New York, New York, NY, USA
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Zuolin Cheng
14Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA, USA
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Guoqiang Yu
14Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA, USA
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John Hardy
15Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London, UK
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Giovanni Coppola
10Departments of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
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Shiaoching Gong
3Helen and Robert Appel Alzheimer’s Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
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Fei Wang
16Department of Population Health Sciences, Weill Cornell Medical College. New York, NY, USA
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Michael A. DeTure
17Mayo Clinic, Jacksonville, Florida, USA
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Bin Zhang
7Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, NY, USA
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Lei Xie
12Institute for Computational Biomedicine, Dept. of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
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Dennis W. Dickson
17Mayo Clinic, Jacksonville, Florida, USA
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Wenjie Luo
3Helen and Robert Appel Alzheimer’s Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
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Li Gan
1Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA
2Gladstone Institute of Neurological Disease, San Francisco, CA, USA
3Helen and Robert Appel Alzheimer’s Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
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  • For correspondence: lig2033@med.cornell.edu
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ABSTRACT

The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). In this study, we identified a subpopulation of microglia with disease-enhancing proinflammatory signatures associated with the R47H mutation in human AD brains and tauopathy mouse brains. Using transcriptomic analysis at the single-nuclei level from AD patients with the R47H or the common variant (CV)-TREM2 with matched sex, pathology and APOE status, we found that the R47H mutation was associated with cell type- and sex-specific transcriptional changes in human AD brains, with microglia exhibiting the most robust alterations. Further characterization revealed that R47H-associated microglial subpopulations had enhanced inflammatory signatures including hyperactivation of Akt, one of the signaling pathways downstream of TREM2. In a newly-generated tauopathy knock-in mouse model expressing one allele of human TREM2 (hTREM2) with either the R47H mutation or CV, 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 significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Syk-Akt-signaling, and elevation of a subset of disease-associated microglial signatures. Strikingly, pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures induced by R47H in primary microglia treated with tau fibrils. By unraveling the disease-enhancing properties of the R47H mutation in mouse and human, our findings shed light on an immune-linked AD subtype and provide new directions for modulating microglial immune responses to treat AD.

Competing Interest Statement

The authors have declared no competing interest.

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AD-linked R47H-TREM2 mutation induces disease-enhancing proinflammatory microglial states in mice and humans
Faten A. Sayed, Lay Kodama, Joe C. Udeochu, Li Fan, Gillian K. Carling, David Le, Qingyun Li, Lu Zhou, Hansruedi Mathys, Minghui Wang, Xiang Niu, Linas Mazutis, Xueqiao Jiang, Xueting Wang, Man Ying Wong, Fuying Gao, Maria Telpoukhovskaia, Tara E. Tracy, Georgia Frost, Yungui Zhou, Yaqiao Li, Matthew Brendel, Yue Qiu, Zuolin Cheng, Guoqiang Yu, John Hardy, Giovanni Coppola, Shiaoching Gong, Fei Wang, Michael A. DeTure, Bin Zhang, Lei Xie, Dennis W. Dickson, Wenjie Luo, Li Gan
bioRxiv 2020.07.24.218719; doi: https://doi.org/10.1101/2020.07.24.218719
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AD-linked R47H-TREM2 mutation induces disease-enhancing proinflammatory microglial states in mice and humans
Faten A. Sayed, Lay Kodama, Joe C. Udeochu, Li Fan, Gillian K. Carling, David Le, Qingyun Li, Lu Zhou, Hansruedi Mathys, Minghui Wang, Xiang Niu, Linas Mazutis, Xueqiao Jiang, Xueting Wang, Man Ying Wong, Fuying Gao, Maria Telpoukhovskaia, Tara E. Tracy, Georgia Frost, Yungui Zhou, Yaqiao Li, Matthew Brendel, Yue Qiu, Zuolin Cheng, Guoqiang Yu, John Hardy, Giovanni Coppola, Shiaoching Gong, Fei Wang, Michael A. DeTure, Bin Zhang, Lei Xie, Dennis W. Dickson, Wenjie Luo, Li Gan
bioRxiv 2020.07.24.218719; doi: https://doi.org/10.1101/2020.07.24.218719

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