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University Hospitals Cleveland Medical Center, Case Western Reserve University, Louis Stokes Cleveland VA Medical Center
Min-Kyoo Shin1,2,3,4,31, Edwin Vázquez-Rosa1,2,3,4,31, Yeojung Koh1,2,3,4, Matasha Dhar1,2,3,4, Kalyani Chaubey1,2,3,4, Coral J. Cintrón-Pérez1,2,3,4, Sarah Barker1,2,3,4, Emiko Miller1,2,3,4, Kathryn Franke1,2,3,4, Maria F. Noterman5, Divya Seth4,6, Rachael S. Allen7,8, Cara T. Motz7,8, Sriganesh Ramachandra Rao9,10, Lara A. Skelton9,10, Machelle T. Pardue7,8, Steven J. Fliesler9,10, Chao Wang11, Tara E. Tracy12, Li Gan13, Daniel J. Liebl14, Jude P.J. Savarraj15, Glenda L.Torres15, Hilda Ahnstedt16, Louise D. McCullough16, Ryan S. Kitagawa15, H. Alex Choi15, Pengyue Zhang17, Yuan Hou18, Chien-Wei Chiang17, Lang Li17, Francisco Ortiz19, Jessica A. Kilgore19, Noelle S. Williams19, Victoria C. Whitehair20,21, Tamar Gefen22,23, Margaret E. Flanagan23,24, Jonathan S. Stamler1,4,6, Mukesh K. Jain1,6, Allison Kraus25, Feixiong Cheng18,26,27, James D. Reynolds1,4,28, Andrew A. Pieper1,2,3,4,29,30,32,*
1Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
2Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA
3Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center; Cleveland, OH, USA
4Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
5Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA
6Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
7Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Atlanta, GA, USA
8Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, US
9Departments of Ophthalmology and Biochemistry, and the Neuroscience Graduate Program, SUNY-University at Buffalo, Buffalo, NY, USA
10Research Service, VA Western NY Healthcare System, Buffalo, NY, USA
11Gladstone Institute of Neurological Disease, San Francisco, CA, USA
12The Buck Institute, Novato, CA, USA
13Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY, USA
14The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
15Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
16Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
17Department of Biomedical Informatics, College of Medicine, Ohio State University, Columbus, OH, USA
18Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
19Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA
20MetroHealth Rehabilitation Institute, The MetroHealth System, Cleveland, OH
21Department of Physical Medicine and Rehabilitation, Case Western Reserve University, School of Medicine, Cleveland, OH USA
22Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
23Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
24Department of Pathology, Northwestern University, Chicago, IL, USA
25Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH, USA
26Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
27Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA
28Departments of Anesthesiology & Perioperative Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
29Weill Cornell Autism Research Program, Weill Cornell Medicine of Cornell University, New York, NY, USA
30Department of Neuroscience, Case Western Reserve University, School of Medicine, Cleveland, OH, USA
31These authors contributed equally
32Lead contact
*Corresponding author
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.
Keywords : neuroprotection, traumatic brain injury, Alzheimer’s disease, acetylation, tau, neurodegeneration, omigapil, congenital muscular dystrophy, salsalate, diflunisal, P7C3
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