Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression

Jessica E. Rexach; Damon Polioudakis; Anna Yin; Vivek Swarup; Timothy S. Chang; Tam Nguyen; Arjun Sarkar; Lawrence Chen; Jerry Huang; Li-Chun Lin; William Seeley; John Q. Trojanowski; Dheeraj Malhotra; Daniel H. Geschwind

Cell Reports (Nov 2020)

Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression

Jessica E. Rexach,
Damon Polioudakis,
Anna Yin,
Vivek Swarup,
Timothy S. Chang,
Tam Nguyen,
Arjun Sarkar,
Lawrence Chen,
Jerry Huang,
Li-Chun Lin,
William Seeley,
John Q. Trojanowski,
Dheeraj Malhotra,
Daniel H. Geschwind

Affiliations

Jessica E. Rexach: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Damon Polioudakis: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Anna Yin: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Vivek Swarup: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Timothy S. Chang: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Tam Nguyen: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Arjun Sarkar: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Lawrence Chen: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Jerry Huang: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Li-Chun Lin: Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
William Seeley: Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
John Q. Trojanowski: Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
Dheeraj Malhotra: Neuroscience and Rare Diseases, Roche Pharma Research and Early Development, F. Hoffman-LaRoche, Basel, Switzerland
Daniel H. Geschwind: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA 90095, USA; Corresponding author

Journal volume & issue: Vol. 33, no. 7
p. 108398

Abstract

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Summary: To understand how neural-immune-associated genes and pathways contribute to neurodegenerative disease pathophysiology, we performed a systematic functional genomic analysis in purified microglia and bulk tissue from mouse and human AD, FTD, and PSP. We uncover a complex temporal trajectory of microglial-immune pathways involving the type 1 interferon response associated with tau pathology in the early stages, followed by later signatures of partial immune suppression and, subsequently, the type 2 interferon response. We find that genetic risk for dementias shows disease-specific patterns of pathway enrichment. We identify drivers of two gene co-expression modules conserved from mouse to human, representing competing arms of microglial-immune activation (NAct) and suppression (NSupp) in neurodegeneration. We validate our findings by using chemogenetics, experimental perturbation data, and single-cell sequencing in post-mortem brains. Our results refine the understanding of stage- and disease-specific microglial responses, implicate microglial viral defense pathways in dementia pathophysiology, and highlight therapeutic windows.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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