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Highlights

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  Brain injury induces Alzheimer's disease-like neuronal ac-tau

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  Neurodegenerative brain injury is reflected by ac-tau blood levels in mice and people

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  Decreasing ac-tau after brain injury at multiple signaling nodes is neuroprotective

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  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.

Graphical abstract

Keywords

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

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Article Info

Publication History

Published: April 13, 2021

Accepted: March 15, 2021

Received in revised form: January 21, 2021

Received: October 5, 2020

Identification

DOI: https://doi.org/10.1016/j.cell.2021.03.032

Copyright

Published by Elsevier Inc.

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