期刊
CELL REPORTS
卷 36, 期 12, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.109720
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资金
- NIH [RF1NS083704-05A1, R01NS083704, R21NS077089, R21NS093442, R01NS116051]
- AIM CoBRE Center [P20GM121176-04]
- University of New Mexico (UNM) Health Sciences Center Bridge Funding
- UNM Department of Molecular Genetics and Microbiology intradepartmental grant
- Dr. Stephanie Ruby travel award
- Alzheimer's Disease Core Center from the National Institute on Aging (NIA) [P30AG013854]
- New Mexico Alzheimer's Disease Research Center from NIA [P20AG068077-01]
Pathological hyperphosphorylation and aggregation of tau, along with neuroinflammation driven by IL-1 beta, are key features of tauopathies. Research shows that pTau primes and activates IL-1 beta through MyD88- and NLRP3-ASC-dependent pathways in myeloid cells, including microglia, leading to tau pathology and cognitive dysfunction.
Pathological hyperphosphorylation and aggregation of tau (pTau) and neuroinflammation, driven by interleukin-1 beta (IL-1 beta), are the major hallmarks of tauopathies. Here, we show that pTau primes and activates IL-1 beta. First, RNA-sequence analysis suggests paired-helical filaments (PHFs) from human tauopathy brain primes nuclear factor kappa B (NF-kappa B), chemokine, and IL-1 beta signaling clusters in human primary microglia. Treating microglia with pTau-containing neuronal media, exosomes, or PHFs causes IL-1 beta activation, which is NLRP3, ASC, and caspase-1 dependent. Suppression of pTau or ASC reduces tau pathology and inflammasome activation in rTg4510 and hTau mice, respectively. Although the deletion of MyD88 prevents both IL-1 beta expression and activation in the hTau mouse model of tauopathy, ASC deficiency in myeloid cells reduces pTau-induced IL-1 beta activation and improves cognitive function in hTau mice. Finally, pTau burden co-exists with elevated IL-1 beta and ASC in autopsy brains of human tauopathies. Together, our results suggest pTau activates IL-1 beta via MyD88- and NLRP3-ASC-dependent pathways in myeloid cells, including microglia.
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