Reducing acetylated tau is neuroprotective in brain injury

Min Kyoo Shin, Edwin Vázquez-Rosa, Yeojung Koh, Matasha Dhar, Kalyani Chaubey, Coral J. Cintrón-Pérez, Sarah Barker, Emiko Miller, Kathryn Franke, Maria F. Noterman, Divya Seth, Rachael S. Allen, Cara T. Motz, Sriganesh Ramachandra Rao, Lara A. Skelton, Machelle T. Pardue, Steven J. Fliesler, Chao Wang, Tara E. Tracy, Li GanDaniel J. Liebl, Jude P.J. Savarraj, Glenda L. Torres, Hilda Ahnstedt, Louise D. McCullough, Ryan S. Kitagawa, H. Alex Choi, Pengyue Zhang, Yuan Hou, Chien Wei Chiang, Lang Li, Francisco Ortiz, Jessica A. Kilgore, Noelle S. Williams, Victoria C. Whitehair, Tamar Gefen, Margaret E. Flanagan, Jonathan S. Stamler, Mukesh K. Jain, Allison Kraus, Feixiong Cheng, James D. Reynolds, Andrew A. Pieper

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2715-2732.e23
JournalCell
Volume184
Issue number10
DOIs
StatePublished - May 13 2021

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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