期刊
CELL
卷 184, 期 10, 页码 2715-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2021.03.032
关键词
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资金
- NIH [P30 AG013854 24]
- NIH/NIA [1 P30 AGO62428-01]
- Brockman Foundation
- Elizabeth Ring Mather and William Gwinn Mather Fund
- S. Livingston Samuel Mather Trust
- G.R. Lincoln Family Foundation
- Wick Foundation
- Leonard Krieger Fund of the Cleveland Foundation
- Alzheimer's Disease Research, a program of BrightFocus Foundation [A2019551F]
- Allen Initiative in Brain Health and Cognitive Impairment [19PABH134580006-AHA]
- Free Radical and Radiation Biology, University of Iowa [T32 CA078586]
- NIA/NIH [RO1AG066707, KO8AG065463, RO1AG062566]
- Miami Project to Cure Paralysis
- NIH/NINDS [NS098740]
- VA BLRD MERIT Award [2 101 BXOO2439-04A1]
- Department of Veterans Affairs
- National Center for Advancing Translational Sciences (NCATS/NIH) [UL1TR001412]
- Department of Veterans Affairs [CDA-2 RX002928]
Traumatic brain injury induces tau acetylation, leading to neurodegeneration and neurobehavioral impairment. Protecting mice from TBI can be achieved by blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1. Ac-tau may serve as a therapeutic target and potential blood biomarker of TBI.
Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.
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