Reducing acetylated tau is neuroprotective in brain injury
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 Si...
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| Vydáno v: | Cell Ročník 184; číslo 10; s. 2715 |
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| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
13.05.2021
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| ISSN: | 1097-4172, 1097-4172 |
| On-line přístup: | Zjistit podrobnosti o přístupu |
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| 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. |
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| AbstractList | 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.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. 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. |
| Author | Chiang, Chien-Wei Barker, Sarah Motz, Cara T Cheng, Feixiong Gan, Li Noterman, Maria F Vázquez-Rosa, Edwin Rao, Sriganesh Ramachandra Koh, Yeojung Kraus, Allison Jain, Mukesh K Tracy, Tara E Chaubey, Kalyani Fliesler, Steven J Torres, Glenda L Savarraj, Jude P J Franke, Kathryn Dhar, Matasha Hou, Yuan Whitehair, Victoria C Flanagan, Margaret E McCullough, Louise D Shin, Min-Kyoo Allen, Rachael S Ahnstedt, Hilda Kitagawa, Ryan S Li, Lang Pardue, Machelle T Liebl, Daniel J Choi, H Alex Pieper, Andrew A Seth, Divya Miller, Emiko Ortiz, Francisco Williams, Noelle S Gefen, Tamar Wang, Chao Reynolds, James D Cintrón-Pérez, Coral J Stamler, Jonathan S Zhang, Pengyue Skelton, Lara A Kilgore, Jessica A |
| Author_xml | – sequence: 1 givenname: Min-Kyoo surname: Shin fullname: Shin, Min-Kyoo organization: Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center; Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA – sequence: 2 givenname: Edwin surname: Vázquez-Rosa fullname: Vázquez-Rosa, Edwin organization: Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center; Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA – sequence: 3 givenname: Yeojung surname: Koh fullname: Koh, Yeojung organization: Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center; Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA – sequence: 4 givenname: Matasha surname: Dhar fullname: Dhar, Matasha organization: Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center; Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA – sequence: 5 givenname: Kalyani surname: Chaubey fullname: Chaubey, Kalyani organization: Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA; 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Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA – sequence: 8 givenname: Emiko surname: Miller fullname: Miller, Emiko organization: Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center; Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA – sequence: 9 givenname: Kathryn surname: Franke fullname: Franke, Kathryn organization: Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center; Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA – sequence: 10 givenname: Maria F surname: Noterman fullname: Noterman, Maria F organization: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA – sequence: 11 givenname: Divya surname: Seth fullname: Seth, Divya organization: Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USA – sequence: 12 givenname: Rachael S surname: Allen fullname: Allen, Rachael S organization: Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Atlanta, GA, USA; Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, US – sequence: 13 givenname: Cara T surname: Motz fullname: Motz, Cara T organization: Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Atlanta, GA, USA; Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, US – sequence: 14 givenname: Sriganesh Ramachandra surname: Rao fullname: Rao, Sriganesh Ramachandra organization: Departments of Ophthalmology and Biochemistry, and the Neuroscience Graduate Program, SUNY-University at Buffalo, Buffalo, NY, USA; Research Service, VA Western NY Healthcare System, Buffalo, NY, USA – sequence: 15 givenname: Lara A surname: Skelton fullname: Skelton, Lara A organization: Departments of Ophthalmology and Biochemistry, and the Neuroscience Graduate Program, SUNY-University at Buffalo, Buffalo, NY, USA; Research Service, VA Western NY Healthcare System, Buffalo, NY, USA – sequence: 16 givenname: Machelle T surname: Pardue fullname: Pardue, Machelle T organization: Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Atlanta, GA, USA; Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, US – sequence: 17 givenname: Steven J surname: Fliesler fullname: Fliesler, Steven J organization: Departments of Ophthalmology and Biochemistry, and the Neuroscience Graduate Program, SUNY-University at Buffalo, Buffalo, NY, USA; Research Service, VA Western NY Healthcare System, Buffalo, NY, USA – sequence: 18 givenname: Chao surname: Wang fullname: Wang, Chao organization: Gladstone Institute of Neurological Disease, San Francisco, CA, USA – sequence: 19 givenname: Tara E surname: Tracy fullname: Tracy, Tara E organization: The Buck Institute, Novato, CA, USA – sequence: 20 givenname: Li surname: Gan fullname: Gan, Li organization: Helen and Robert Appel Alzheimer's Disease Research Institute, Weill Cornell Medicine, New York, NY, USA – sequence: 21 givenname: Daniel J surname: Liebl fullname: Liebl, Daniel J organization: The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA – sequence: 22 givenname: Jude P J surname: Savarraj fullname: Savarraj, Jude P J organization: Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA – sequence: 23 givenname: Glenda L surname: Torres fullname: Torres, Glenda L organization: Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA – sequence: 24 givenname: Hilda surname: Ahnstedt fullname: Ahnstedt, Hilda organization: Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA – sequence: 25 givenname: Louise D surname: McCullough fullname: McCullough, Louise D organization: Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA – sequence: 26 givenname: Ryan S surname: Kitagawa fullname: Kitagawa, Ryan S organization: Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA – sequence: 27 givenname: H Alex surname: Choi fullname: Choi, H Alex organization: Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA – sequence: 28 givenname: Pengyue surname: Zhang fullname: Zhang, Pengyue organization: Department of Biomedical Informatics, College of Medicine, Ohio State University, Columbus, OH, USA – sequence: 29 givenname: Yuan surname: Hou fullname: Hou, Yuan organization: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA – sequence: 30 givenname: Chien-Wei surname: Chiang fullname: Chiang, Chien-Wei organization: Department of Biomedical Informatics, College of Medicine, Ohio State University, Columbus, OH, USA – sequence: 31 givenname: Lang surname: Li fullname: Li, Lang organization: Department of Biomedical Informatics, College of Medicine, Ohio State University, Columbus, OH, USA – sequence: 32 givenname: Francisco surname: Ortiz fullname: Ortiz, Francisco organization: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA – sequence: 33 givenname: Jessica A surname: Kilgore fullname: Kilgore, Jessica A organization: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA – sequence: 34 givenname: Noelle S surname: Williams fullname: Williams, Noelle S organization: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA – sequence: 35 givenname: Victoria C surname: Whitehair fullname: Whitehair, Victoria C organization: MetroHealth Rehabilitation Institute, The MetroHealth System, Cleveland, OH; Department of Physical Medicine and Rehabilitation, Case Western Reserve University, School of Medicine, Cleveland, OH USA – sequence: 36 givenname: Tamar surname: Gefen fullname: Gefen, Tamar organization: Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA – sequence: 37 givenname: Margaret E surname: Flanagan fullname: Flanagan, Margaret E organization: Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Department of Pathology, Northwestern University, Chicago, IL, USA – sequence: 38 givenname: Jonathan S surname: Stamler fullname: Stamler, Jonathan S organization: Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; 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Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Departments of Anesthesiology & Perioperative Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USA – sequence: 43 givenname: Andrew A surname: Pieper fullname: Pieper, Andrew A email: andrew.pieper@harringtondiscovery.org organization: Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center; Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Weill Cornell Autism Research Program, Weill Cornell Medicine of Cornell University, New York, NY, USA; Department of Neuroscience, Case Western Reserve University, School of Medicine, Cleveland, OH, USA. Electronic address: andrew.pieper@harringtondiscovery.org |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33852912$$D View this record in MEDLINE/PubMed |
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| Copyright | Published by Elsevier Inc. |
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| DOI | 10.1016/j.cell.2021.03.032 |
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| Keywords | acetylation congenital muscular dystrophy omigapil P7C3 Alzheimer’s disease salsalate neuroprotection diflunisal neurodegeneration traumatic brain injury tau |
| Language | English |
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| References | 35590136 - Med. 2021 Jun 11;2(6):637-639 33953376 - Nat Rev Neurosci. 2021 Jun;22(6):325 33888906 - Nat Rev Drug Discov. 2021 Jun;20(6):424 |
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| Snippet | 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... |
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| SubjectTerms | Acetylation Alzheimer Disease - etiology Alzheimer Disease - metabolism Alzheimer Disease - prevention & control Animals Anti-Inflammatory Agents, Non-Steroidal - therapeutic use Biomarkers - blood Biomarkers - metabolism Brain Injuries, Traumatic - complications Brain Injuries, Traumatic - metabolism Cell Line Diflunisal - therapeutic use Female Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) Humans Male Mice Mice, Inbred C57BL Neurons - metabolism Neuroprotection p300-CBP Transcription Factors - antagonists & inhibitors p300-CBP Transcription Factors - metabolism Salicylates - therapeutic use Sirtuin 1 - metabolism tau Proteins - blood tau Proteins - metabolism |
| Title | Reducing acetylated tau is neuroprotective in brain injury |
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