Cell
Volume 184, Issue 10, 13 May 2021, Pages 2715-2732.e23
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Article
Reducing acetylated tau is neuroprotective in brain injury

https://doi.org/10.1016/j.cell.2021.03.032Get rights and content
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Highlights

  • 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 disease

Summary

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.

Keywords

neuroprotection
traumatic brain injury
Alzheimer’s disease
acetylation
tau
neurodegeneration
omigapil
congenital muscular dystrophy
salsalate
diflunisal
P7C3

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These authors contributed equally

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