Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression.
Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression.
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Tau病理学驱动痴呆风险相关基因网络走向慢性炎症状态和免疫抑制
DOI：
10.1016/j.celrep.2020.108398
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发表时间：
2020-11-17
期刊：
影响因子：
8.8
通讯作者：
Geschwind DH
中科院分区：
文献类型：
--
作者：
Rexach JE;Polioudakis D;Yin A;Swarup V;Chang TS;Nguyen T;Sarkar A;Chen L;Huang J;Lin LC;Seeley W;Trojanowski JQ;Malhotra D;Geschwind DH
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. 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.
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影响因子：
9.8
作者：
Allen, Mariet;Carrasquillo, Minerva M.;Funk, Cory;Heavner, Benjamin D.;Zou, Fanggeng;Younkin, Curtis S.;Burgess, Jeremy D.;Chai, High-Seng;Crook, Julia;Eddy, James A.;Li, Hongdong;Logsdon, Ben;Peters, Mette A.;Dang, Kristen K.;Wang, Xue;Serie, Daniel;Wang, Chen;Thuy Nguyen;Lincoln, Sarah;Malphrus, Kimberly;Bisceglio, Gina;Li, Ma;Golde, Todd E.;Mangravite, Lara M.;Asmann, Yan;Price, Nathan D.;Petersen, Ronald C.;Graff-Radford, Neill R.;Dickson, Dennis W.;Younkin, Steven G.;Ertekin-Taner, Nilufer
通讯作者：
Ertekin-Taner, Nilufer
影响因子：
32.4
作者：
Hammond, Timothy R.;Dufort, Connor;Stevens, Beth
通讯作者：
Stevens, Beth
影响因子：
3.5
作者：
Chen-Plotkin, Alice S.;Geser, Felix;Lee, Virginia M. -Y.
通讯作者：
Lee, Virginia M. -Y.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
25
作者：
Grubman, Alexandra;Chew, Gabriel;Polo, Jose M.
通讯作者：
Polo, Jose M.