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AD-Linked TREM2 Mutation Induces Unique Microglial States Associated with Toxic Function in Tauopathy

68 Pages Posted: 16 Jul 2019 Sneak Peek Status: Review Complete

See all articles by Faten A. Sayed

Faten A. Sayed

University of California, San Francisco (UCSF)

Lay Kodama

Gladstone Institute of Neurological Disease

Joe Udeochu

Gladstone Institute of Neurological Disease

Hansruedi Mathys

Massachusetts Institute of Technology (MIT)

David Le

Gladstone Institute of Neurological Disease

Xiang Niu

Weill Cornell Medical College

Linas Mazutis

Memorial Sloan Kettering Cancer Center - Program for Computational and Systems Biology

Xueqiao Jiang

Massachusetts Institute of Technology (MIT)

Tara E. Tracy

Gladstone Institute of Neurological Disease

Fuying Gao

University of California, Los Angeles (UCLA)

Maria Telpoukhovskaia

Gladstone Institute of Neurological Disease

Yueming Li

Cornell University

Georgia Frost

Cornell University

Yungui Zhou

Gladstone Institute of Neurological Disease

Yaqiao Li

University of California, San Francisco (UCSF) - Gladstone Institute of Neurological Disease

John Hardy

University College London - Department of Molecular Neuroscience

Giovanni Coppola

University of California, Los Angeles (UCLA) - Department of Neurology

Li-Huei Tsai

Massachusetts Institute of Technology (MIT)

Li Gan

Gladstone Institute of Neurological Disease

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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). To understand its pathogenicity, we generated knock-in mice in which mouse Trem2 was replaced with wild-type or R47H human TREM2. One allele of R47H-hTREM2 was sufficient to induce cognitive deficits and alter synaptic transmission. In knock-in mice with tau inclusions, R47H-hTREM2 exacerbated spatial learning and memory deficits only in female mice. Bulk and single-nuclei RNA-sequencing of hippocampal tissue from female tauopathy mice revealed R47H-induced upregulation of cytokine signaling and microglial clusters with unique R47H-associated signatures. Single-nuclei RNA-sequencing of cortex from AD patients with and without R47H-TREM2 established transcriptomic changes in glial populations that correlated significantly with those observed in the R47H tauopathy mouse model. By unraveling disease-enhancing properties of the R47H mutation, our findings provide new directions for developing microglia-targeted AD therapies.

Keywords: TREM2, R47H, microglia, inflammation, tauopathy, single-nuclei RNA-sequencing, Alzheimer's disease, memory impairment, synaptic function

Suggested Citation

Sayed, Faten A. and Kodama, Lay and Udeochu, Joe and Mathys, Hansruedi and Le, David and Niu, Xiang and Mazutis, Linas and Jiang, Xueqiao and Tracy, Tara E. and Gao, Fuying and Telpoukhovskaia, Maria and Li, Yueming and Frost, Georgia and Zhou, Yungui and Li, Yaqiao and Hardy, John and Coppola, Giovanni and Tsai, Li-Huei and Gan, Li, AD-Linked TREM2 Mutation Induces Unique Microglial States Associated with Toxic Function in Tauopathy (July 16, 2019). CELL-D-19-01794. Available at SSRN: https://ssrn.com/abstract=3420370 or http://dx.doi.org/10.2139/ssrn.3420370
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Faten A. Sayed

University of California, San Francisco (UCSF) ( email )

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Lay Kodama

Gladstone Institute of Neurological Disease ( email )

1650 Owens Street
San Francisco, CA 94158
United States

Joe Udeochu

Gladstone Institute of Neurological Disease

1650 Owens Street
San Francisco, CA 94158
United States

Hansruedi Mathys

Massachusetts Institute of Technology (MIT)

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

David Le

Gladstone Institute of Neurological Disease

1650 Owens Street
San Francisco, CA 94158
United States

Xiang Niu

Weill Cornell Medical College

1300 York Avenue
P.O. Box 24144
New York, NY 10065
United States

Linas Mazutis

Memorial Sloan Kettering Cancer Center - Program for Computational and Systems Biology

New York, NY
United States

Xueqiao Jiang

Massachusetts Institute of Technology (MIT)

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Tara E. Tracy

Gladstone Institute of Neurological Disease

1650 Owens Street
San Francisco, CA 94158
United States

Fuying Gao

University of California, Los Angeles (UCLA)

405 Hilgard Avenue
Box 951361
Los Angeles, CA 90095
United States

Maria Telpoukhovskaia

Gladstone Institute of Neurological Disease

1650 Owens Street
San Francisco, CA 94158
United States

Yueming Li

Cornell University

Ithaca, NY 14853
United States

Georgia Frost

Cornell University

Ithaca, NY 14853
United States

Yungui Zhou

Gladstone Institute of Neurological Disease

1650 Owens Street
San Francisco, CA 94158
United States

Yaqiao Li

University of California, San Francisco (UCSF) - Gladstone Institute of Neurological Disease

1650 Owens Street
San Francisco, CA 94158
United States

John Hardy

University College London - Department of Molecular Neuroscience

Gower Street
London, WC1E 6BT
United Kingdom

Giovanni Coppola

University of California, Los Angeles (UCLA) - Department of Neurology

1000 Veteran Avenue, Box 956939
Los Angeles, CA 90095-6939
United States

Li-Huei Tsai

Massachusetts Institute of Technology (MIT)

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Li Gan (Contact Author)

Gladstone Institute of Neurological Disease ( email )

1650 Owens Street
San Francisco, CA 94158
United States

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