Journal
CELL REPORTS
Volume 33, Issue 7, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.108398
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Funding
- Takeda Pharmaceuticals
- Rainwater Charitable Foundation
- Roche Pharmaceuticals
- BrightFocus
- NIH [5R25 NS065723, K08 NS105916, AG023501, AG019724]
- Fineberg Foundation
- John Douglas French Alzheimer's Foundation
- Bluefield Project to Cure FTD
- NIH Alzheimer's Disease Core Center [P30AG010123]
- NIH Center on Alpha-synuclein Strains in Alzheimer Disease & Related Dementias [U19-AG062418]
- NIH Frontotemporal Dementias: Genotypes and Phenotypes [P01-AG017586]
- NIH Center without Walls for Imaging Proteinopathies with PET (CW2IP2) [U19-NS110456U54]
- NIH Connect-TBI [U54-RFA-NS-19-030]
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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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