Journal article
Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression
Cell reports (Cambridge), Vol.33(7), pp.108398-108398
11/17/2020
DOI: 10.1016/j.celrep.2020.108398
PMID: 33207193
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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•Significant changes in microglial-immune signaling mark stages of neurodegeneration•Pro-inflammatory pathways yield to early interferon-driven immune suppression•A key hub in the immune suppression module, USP18, modulates this response•Validation of chemogenetic predictions identifies drugs modulating microglial function
Rexach et al. use transcriptional network analysis to define dynamic microglial transitions across neurodegeneration, discovering that three dementias with tau pathology involve dysregulated microglial viral and antiviral pathways. Bio-informatics coupled with experimental validation identifies regulatory drivers, implicating double-stranded RNA and interferon-response genes as drivers of early immune suppression in disease.
Details
- Title: Subtitle
- Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression
- Creators
- Jessica E Rexach - University of California, Los AngelesLi-Chun Lin - University of California, San FranciscoDamon Polioudakis - University of California, Los AngelesAnna Yin - University of California, Los AngelesVivek Swarup - University of California, Los AngelesTimothy S Chang - University of California, Los AngelesTam Nguyen - University of California, Los AngelesArjun Sarkar - University of California, Los AngelesLawrence Chen - University of California, Los AngelesJerry Huang - University of California, Los AngelesWilliam Seeley - University of California, San FranciscoJohn Q Trojanowski - University of PennsylvaniaDheeraj Malhotra - Hoffmann-La RocheDaniel H Geschwind - University of California, Los Angeles
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.33(7), pp.108398-108398
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.celrep.2020.108398
- PMID
- 33207193
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Grant note
- name: Takeda Pharmaceuticals; DOI: 10.13039/100016608, name: Rainwater Charitable Foundation; name: Roche Pharmaceuticals; DOI: 10.13039/100006312, name: BrightFocus; DOI: 10.13039/100000002, name: NIH, award: 5R25 NS065723, K08 NS105916; name: Fineberg Foundation; name: John Douglas French Alzheimer’s Foundation; DOI: 10.13039/100000002, name: NIH, award: AG023501, AG019724; DOI: 10.13039/100016608, name: Rainwater Charitable Foundation; name: Bluefield Project to Cure FTD; DOI: 10.13039/100000002, name: NIH, award: P30-AG010123, U19-AG062418, P01-AG017586, U19-NS110456U54, CW2IP2, U54-RFA-NS-19-030 Connect-TBI
- Language
- English
- Date published
- 11/17/2020
- Academic Unit
- Neurology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984184143002771
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