|Title||Reducing acetylated tau is neuroprotective in brain injury.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Shin M-K, Vázquez-Rosa E, Koh Y, Dhar M, Chaubey K, Cintrón-Pérez CJ, Barker S, Miller E, Franke K, Noterman MF, Seth D, Allen RS, Motz CT, Rao SRamachandr, Skelton LA, Pardue MT, Fliesler SJ, Wang C, Tracy TE, Gan L, Liebl DJ, Savarraj JPJ, Torres GL, Ahnstedt H, McCullough LD, Kitagawa RS, H Choi A, Zhang P, Hou Y, Chiang C-W, Li L, Ortiz F, Kilgore JA, Williams NS, Whitehair VC, Gefen T, Flanagan ME, Stamler JS, Jain MK, Kraus A, Cheng F, Reynolds JD, Pieper AA|
|Date Published||2021 Apr 10|
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.