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Cited by 94Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

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

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Rexach, Jessica E., Polioudakis, Damon, Yin, Anna, Swarup, Vivek, Chang, Timothy S., Nguyen, Tam, Sarkar, Arjun, Chen, Lawrence +6 more·2020·Cell Reports
DOI 10.1016/j.celrep.2020.108398PMC PMC7842189
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Abstract

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.

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  • The observed tau effect is reminiscent of transition of microglial response from the neuroimmune activation state (NAct) to an immunosuppressed state (NSupp) in the context of tau-associated neurodegeneration networks.

    “This is reminiscent of transition of microglial response from the neuroimmune activation state (NAct) to an immunosuppressed state (NSupp) in the context of tau-associated neurodegeneration networks (34).”

    From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [34]

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Authors
Rexach, J. E., Polioudakis, D., Yin, A., Swarup, V., Chang, T. S., Nguyen, T., Sarkar, A., Chen, L., Huang, J., Lin, L.-C., Seeley, W., Trojanowski, J. Q., Malhotra, D., & Geschwind, D. H.
Affiliations
  • University of California, Los Angeles (US)
  • University of California, San Francisco (US)
  • University of Pennsylvania (US)
  • F. Hoffmann-La Roche AG (CH)
Corresponding author
Geschwind, Daniel H.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2020-11
Volume
33
Issue
7
Pages
108398
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2020.108398
PMC
PMC7842189
OpenAlex
W3098926190
Cited by
94
References
97
Citations by year
2026: 9 · 2025: 13 · 2024: 23 · 2023: 20 · 2022: 18 · 2021: 10
FWCI
4.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • eScholarship (California Digital Library) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health
  • BrightFocus Foundation
  • F. Hoffmann-La Roche
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
tau pathology, dementia, microglia, neuroinflammation, immunosuppression, type I interferon response, Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, risk genes, gene co-expression modules, neurodegeneration, chemogenetics, single-cell transcriptomics
MeSH terms
Aged, Animals, Brain, Dementia, Female, Humans, Immunosuppression Therapy, Inflammation, Male, Mice, Inbred C57BL, Risk Factors, tau Proteins, Microglia, Neurodegenerative Diseases, Genetic Predisposition to Disease, Genomics, Tauopathies, Mice, Gene Regulatory Networks, Frontotemporal Dementia, Primary Cell Culture

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