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.
