Abstract
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.
Original language | English (US) |
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Pages (from-to) | 2715-2732.e23 |
Journal | Cell |
Volume | 184 |
Issue number | 10 |
DOIs | |
State | Published - May 13 2021 |
Keywords
- Alzheimer's disease
- P7C3
- acetylation
- congenital muscular dystrophy
- diflunisal
- neurodegeneration
- neuroprotection
- omigapil
- salsalate
- tau
- traumatic brain injury
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology