| Literature DB >> 33852912 |
Min-Kyoo Shin1, Edwin Vázquez-Rosa1, Yeojung Koh1, Matasha Dhar1, Kalyani Chaubey1, Coral J Cintrón-Pérez1, Sarah Barker1, Emiko Miller1, Kathryn Franke1, Maria F Noterman2, Divya Seth3, Rachael S Allen4, Cara T Motz4, Sriganesh Ramachandra Rao5, Lara A Skelton5, Machelle T Pardue4, Steven J Fliesler5, Chao Wang6, Tara E Tracy7, Li Gan8, Daniel J Liebl9, Jude P J Savarraj10, Glenda L Torres10, Hilda Ahnstedt11, Louise D McCullough11, Ryan S Kitagawa10, H Alex Choi10, Pengyue Zhang12, Yuan Hou13, Chien-Wei Chiang12, Lang Li12, Francisco Ortiz14, Jessica A Kilgore14, Noelle S Williams14, Victoria C Whitehair15, Tamar Gefen16, Margaret E Flanagan17, Jonathan S Stamler18, Mukesh K Jain19, Allison Kraus20, Feixiong Cheng21, James D Reynolds22, Andrew A Pieper23.
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. Published by Elsevier Inc.Entities:
Keywords: Alzheimer’s disease; P7C3; acetylation; congenital muscular dystrophy; diflunisal; neurodegeneration; neuroprotection; omigapil; salsalate; tau; traumatic brain injury
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Year: 2021 PMID： 33852912 PMCID： PMC8491234 DOI： 10.1016/j.cell.2021.03.032
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582