Reducing acetylated tau is neuroprotective in brain injury

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.[Display omitted]•Brain injury induces Alzheimer’s disease-like neuronal ac-tau•Neurodegenerative brain injury is reflected by ac-tau blood levels in mice and people•Decreasing ac-tau after brain injury at multiple signaling nodes is neuroprotective•Ac-tau-inhibiting medicines are associated with reduced neurodegenerative diseaseReducing brain injury-induced neuronal tau acetylation is neuroprotective in traumatic brain injury and has a role in Alzheimer’s disease pathogenesis