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 Gan; Daniel 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

doi:10.1016/j.cell.2021.03.032

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 journal › Article › peer-review

41 Scopus citations

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 language	English (US)
Pages (from-to)	2715-2732.e23
Journal	Cell
Volume	184
Issue number	10
DOIs	https://doi.org/10.1016/j.cell.2021.03.032
State	Published - 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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10.1016/j.cell.2021.03.032

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Shin, M. K., Vázquez-Rosa, E., Koh, Y., Dhar, M., Chaubey, K., Cintrón-Pérez, C. J., Barker, S., Miller, E., Franke, K., Noterman, M. F., Seth, D., Allen, R. S., Motz, C. T., Rao, S. R., Skelton, L. A., Pardue, M. T., Fliesler, S. J., Wang, C., Tracy, T. E., ... Pieper, A. A. (2021). Reducing acetylated tau is neuroprotective in brain injury. Cell, 184(10), 2715-2732.e23. https://doi.org/10.1016/j.cell.2021.03.032

Shin, MK, Vázquez-Rosa, E, Koh, Y, Dhar, M, Chaubey, K, Cintrón-Pérez, CJ, Barker, S, Miller, E, Franke, K, Noterman, MF, Seth, D, Allen, RS, Motz, CT, Rao, SR, Skelton, LA, Pardue, MT, Fliesler, SJ, Wang, C, Tracy, TE, Gan, L, Liebl, DJ, Savarraj, JPJ, Torres, GL, Ahnstedt, H, McCullough, LD, Kitagawa, RS, Choi, HA, Zhang, P, Hou, Y, Chiang, CW, Li, L, Ortiz, F, Kilgore, JA, Williams, NS, Whitehair, VC, Gefen, T, Flanagan, ME, Stamler, JS, Jain, MK, Kraus, A, Cheng, F, Reynolds, JD & Pieper, AA 2021, 'Reducing acetylated tau is neuroprotective in brain injury', Cell, vol. 184, no. 10, pp. 2715-2732.e23. https://doi.org/10.1016/j.cell.2021.03.032

@article{ccf429451c6f4bf88a5726478fe441f0,

title = "Reducing acetylated tau is neuroprotective in brain injury",

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

author = "Shin, {Min Kyoo} and Edwin V{\'a}zquez-Rosa and Yeojung Koh and Matasha Dhar and Kalyani Chaubey and Cintr{\'o}n-P{\'e}rez, {Coral J.} and Sarah Barker and Emiko Miller and Kathryn Franke and Noterman, {Maria F.} and Divya Seth and Allen, {Rachael S.} and Motz, {Cara T.} and Rao, {Sriganesh Ramachandra} and Skelton, {Lara A.} and Pardue, {Machelle T.} and Fliesler, {Steven J.} and Chao Wang and Tracy, {Tara E.} and Li Gan and Liebl, {Daniel J.} and Savarraj, {Jude P.J.} and Torres, {Glenda L.} and Hilda Ahnstedt and McCullough, {Louise D.} and Kitagawa, {Ryan S.} and Choi, {H. Alex} and Pengyue Zhang and Yuan Hou and Chiang, {Chien Wei} and Lang Li and Francisco Ortiz and Kilgore, {Jessica A.} and Williams, {Noelle S.} and Whitehair, {Victoria C.} and Tamar Gefen and Flanagan, {Margaret E.} and Stamler, {Jonathan S.} and Jain, {Mukesh K.} and Allison Kraus and Feixiong Cheng and Reynolds, {James D.} and Pieper, {Andrew A.}",

note = "Funding Information: We thank those who provided blood and brain samples, Matthew N. Rasband for βIV-spectrin antibodies, Peter Davies for PHF1 (p-tau S396/S404) antibodies, Mikayla Huntley for tau seeding assay help, and Gloria Lee for providing brain tissue from tau knockout mice. Postmortem brain tissues were provided by the Neuropathology Core of Northwestern University (NIH P30 AG013854 24). We thank the Translational Therapeutics Core of the Cleveland Alzheimer's Disease Research Center (NIH/NIA 1 P30 AGO62428-01) for assisting in the study with human postmortem brain tissues. The SV2 monoclonal antibody developed by K.M. Buckley was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH, and maintained at The University of Iowa, Department of Biology (Iowa City, IA). This work was supported by a grant to A.A.P. from the Brockman Foundation. A.A.P. was also supported by Elizabeth Ring Mather and William Gwinn Mather Fund, S. Livingston Samuel Mather Trust, G.R. Lincoln Family Foundation, Wick Foundation, the Leonard Krieger Fund of the Cleveland Foundation, Gordon and Evie Safran, and Louis Stokes VA Medical Center resources and facilities. Acknowledgment is made to the donors of Alzheimer's Disease Research, a program of BrightFocus Foundation, for support of M.-K.S. in this research (A2019551F). A.A.P. M.K.J. J.D.R. and J.S.S. are supported by Project 19PABH134580006-AHA/Allen Initiative in Brain Health and Cognitive Impairment. E.V.-R. was supported by Free Radical and Radiation Biology, University of Iowa (T32 CA078586). F.C. and A.A.P. are supported together by NIA/NIH (RO1AG066707) and also the Translational Therapeutic Core of the Cleveland Alzheimer's Disease Research Center (NIH/NIA 1 P30 AGO62428-01), which assisted in the study of human postmortem brain tissue and longitudinal analysis of patient data. D.J.L. was supported by The Miami Project to Cure Paralysis and NIH/NINDS (NS098740). S.J.F. and M.T.P. were supported by VA BLR&D MERIT Award (2 101 BXOO2439-04A1) and Research Career Scientist Awards from Department of Veterans Affairs, with resources of VA Western NY Healthcare System (Buffalo, NY), and Atlanta VA Medical Center (Decatur, GA). S.J.F. was supported by Clinical and Translational Science Award (UL1TR001412) to University of Buffalo from National Center for Advancing Translational Sciences (NCATS/NIH). R.S.A. was supported by Career Development Award (CDA-2 RX002928) from Department of Veterans Affairs. T.G. was supported by NIA/NIH (RO1AG062566). M.E.F. was supported by NIA/NIH (KO8AG065463). M.-K.S. E.V.-R. and A.A.P. designed experiments and interpreted data. M.K.J. and J.D.R. assisted with experimental design and data interpretation. M.-K.S. E.V.-R. Y.K. M.D. K.C. K.F. C.C.-P. S.B. E.M. and M.N. conducted experiments. R.S.A. C.T.M. S.R.R. M.T.P. L.A.S. and S.J.F. supplied brain tissue from acoustic blast overpressure injury. D.J.L. supplied brain tissue from controlled cortical impact injury. C.W. and L.G. provided antibodies to acetylated tau. T.E.T. provided transgenic mouse brain tissue and SV2 immunohistochemical analysis. J.P.J.S. G.L.T. H.A. L.D.M. R.S.K. and H.A.C. collected plasma from human subjects. D.S. and J.S.S. assisted with S-nitrosylation experiments. A.K. and S.B. conducted tau seeding experiments. P.Z. Y.H. C.-W.C. L.L. and F.C. conducted analysis of NSAID usage and incidence of Alzheimer's disease. F.O. J.A.K. and N.S.W. conducted diflunisal pharmacokinetic studies. M.E.F. and T.G. assisted in study of human postmortem brain tissue. V.E.W. assisted in analysis of human plasma samples. A.A.P. M.-K.S. E.V.-R. M.K.J. J.S.S. and J.D.R. wrote the manuscript. All authors reviewed and approved the manuscript. A.A.P. is an inventor on patents related to P7C3. L.G. is a founder of Aeton Therapeutics. No other authors declare competing interests. Funding Information: We thank those who provided blood and brain samples, Matthew N. Rasband for βIV-spectrin antibodies, Peter Davies for PHF1 (p-tau S396/S404) antibodies, Mikayla Huntley for tau seeding assay help, and Gloria Lee for providing brain tissue from tau knockout mice. Postmortem brain tissues were provided by the Neuropathology Core of Northwestern University ( NIH P30 AG013854 24 ). We thank the Translational Therapeutics Core of the Cleveland Alzheimer{\textquoteright}s Disease Research Center ( NIH/NIA 1 P30 AGO62428-01 ) for assisting in the study with human postmortem brain tissues. The SV2 monoclonal antibody developed by K.M. Buckley was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH, and maintained at The University of Iowa, Department of Biology (Iowa City, IA). This work was supported by a grant to A.A.P. from the Brockman Foundation . A.A.P. was also supported by Elizabeth Ring Mather and William Gwinn Mather Fund , S. Livingston Samuel Mather Trust , G.R. Lincoln Family Foundation , Wick Foundation , the Leonard Krieger Fund of the Cleveland Foundation , Gordon and Evie Safran , and Louis Stokes VA Medical Center resources and facilities. Acknowledgment is made to the donors of Alzheimer{\textquoteright}s Disease Research , a program of BrightFocus Foundation , for support of M.-K.S. in this research ( A2019551F ). A.A.P., M.K.J., J.D.R., and J.S.S. are supported by Project 19PABH134580006-AHA/Allen Initiative in Brain Health and Cognitive Impairment . E.V.-R. was supported by Free Radical and Radiation Biology, University of Iowa ( T32 CA078586 ). F.C. and A.A.P. are supported together by NIA/NIH ( RO1AG066707 ) and also the Translational Therapeutic Core of the Cleveland Alzheimer{\textquoteright}s Disease Research Center ( NIH/NIA 1 P30 AGO62428-01 ), which assisted in the study of human postmortem brain tissue and longitudinal analysis of patient data. D.J.L. was supported by The Miami Project to Cure Paralysis and NIH/NINDS ( NS098740 ). S.J.F. and M.T.P. were supported by VA BLR&D MERIT Award ( 2 101 BXOO2439-04A1 ) and Research Career Scientist Awards from Department of Veterans Affairs , with resources of VA Western NY Healthcare System (Buffalo, NY), and Atlanta VA Medical Center (Decatur, GA). S.J.F. was supported by Clinical and Translational Science Award ( UL1TR001412 ) to University of Buffalo from National Center for Advancing Translational Sciences (NCATS/NIH). R.S.A. was supported by Career Development Award ( CDA-2 RX002928 ) from Department of Veterans Affairs . T.G. was supported by NIA/NIH ( RO1AG062566 ). M.E.F. was supported by NIA/NIH ( KO8AG065463 ). Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = may,

day = "13",

doi = "10.1016/j.cell.2021.03.032",

language = "English (US)",

volume = "184",

pages = "2715--2732.e23",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "10",

}

TY - JOUR

T1 - Reducing acetylated tau is neuroprotective in brain injury

AU - Shin, Min Kyoo

AU - Vázquez-Rosa, Edwin

AU - Koh, Yeojung

AU - Dhar, Matasha

AU - Chaubey, Kalyani

AU - Cintrón-Pérez, Coral J.

AU - Barker, Sarah

AU - Miller, Emiko

AU - Franke, Kathryn

AU - Noterman, Maria F.

AU - Seth, Divya

AU - Allen, Rachael S.

AU - Motz, Cara T.

AU - Rao, Sriganesh Ramachandra

AU - Skelton, Lara A.

AU - Pardue, Machelle T.

AU - Fliesler, Steven J.

AU - Wang, Chao

AU - Tracy, Tara E.

AU - Gan, Li

AU - Liebl, Daniel J.

AU - Savarraj, Jude P.J.

AU - Torres, Glenda L.

AU - Ahnstedt, Hilda

AU - McCullough, Louise D.

AU - Kitagawa, Ryan S.

AU - Choi, H. Alex

AU - Zhang, Pengyue

AU - Hou, Yuan

AU - Chiang, Chien Wei

AU - Li, Lang

AU - Ortiz, Francisco

AU - Kilgore, Jessica A.

AU - Williams, Noelle S.

AU - Whitehair, Victoria C.

AU - Gefen, Tamar

AU - Flanagan, Margaret E.

AU - Stamler, Jonathan S.

AU - Jain, Mukesh K.

AU - Kraus, Allison

AU - Cheng, Feixiong

AU - Reynolds, James D.

AU - Pieper, Andrew A.

N1 - Funding Information: We thank those who provided blood and brain samples, Matthew N. Rasband for βIV-spectrin antibodies, Peter Davies for PHF1 (p-tau S396/S404) antibodies, Mikayla Huntley for tau seeding assay help, and Gloria Lee for providing brain tissue from tau knockout mice. Postmortem brain tissues were provided by the Neuropathology Core of Northwestern University (NIH P30 AG013854 24). We thank the Translational Therapeutics Core of the Cleveland Alzheimer's Disease Research Center (NIH/NIA 1 P30 AGO62428-01) for assisting in the study with human postmortem brain tissues. The SV2 monoclonal antibody developed by K.M. Buckley was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH, and maintained at The University of Iowa, Department of Biology (Iowa City, IA). This work was supported by a grant to A.A.P. from the Brockman Foundation. A.A.P. was also supported by Elizabeth Ring Mather and William Gwinn Mather Fund, S. Livingston Samuel Mather Trust, G.R. Lincoln Family Foundation, Wick Foundation, the Leonard Krieger Fund of the Cleveland Foundation, Gordon and Evie Safran, and Louis Stokes VA Medical Center resources and facilities. Acknowledgment is made to the donors of Alzheimer's Disease Research, a program of BrightFocus Foundation, for support of M.-K.S. in this research (A2019551F). A.A.P. M.K.J. J.D.R. and J.S.S. are supported by Project 19PABH134580006-AHA/Allen Initiative in Brain Health and Cognitive Impairment. E.V.-R. was supported by Free Radical and Radiation Biology, University of Iowa (T32 CA078586). F.C. and A.A.P. are supported together by NIA/NIH (RO1AG066707) and also the Translational Therapeutic Core of the Cleveland Alzheimer's Disease Research Center (NIH/NIA 1 P30 AGO62428-01), which assisted in the study of human postmortem brain tissue and longitudinal analysis of patient data. D.J.L. was supported by The Miami Project to Cure Paralysis and NIH/NINDS (NS098740). S.J.F. and M.T.P. were supported by VA BLR&D MERIT Award (2 101 BXOO2439-04A1) and Research Career Scientist Awards from Department of Veterans Affairs, with resources of VA Western NY Healthcare System (Buffalo, NY), and Atlanta VA Medical Center (Decatur, GA). S.J.F. was supported by Clinical and Translational Science Award (UL1TR001412) to University of Buffalo from National Center for Advancing Translational Sciences (NCATS/NIH). R.S.A. was supported by Career Development Award (CDA-2 RX002928) from Department of Veterans Affairs. T.G. was supported by NIA/NIH (RO1AG062566). M.E.F. was supported by NIA/NIH (KO8AG065463). M.-K.S. E.V.-R. and A.A.P. designed experiments and interpreted data. M.K.J. and J.D.R. assisted with experimental design and data interpretation. M.-K.S. E.V.-R. Y.K. M.D. K.C. K.F. C.C.-P. S.B. E.M. and M.N. conducted experiments. R.S.A. C.T.M. S.R.R. M.T.P. L.A.S. and S.J.F. supplied brain tissue from acoustic blast overpressure injury. D.J.L. supplied brain tissue from controlled cortical impact injury. C.W. and L.G. provided antibodies to acetylated tau. T.E.T. provided transgenic mouse brain tissue and SV2 immunohistochemical analysis. J.P.J.S. G.L.T. H.A. L.D.M. R.S.K. and H.A.C. collected plasma from human subjects. D.S. and J.S.S. assisted with S-nitrosylation experiments. A.K. and S.B. conducted tau seeding experiments. P.Z. Y.H. C.-W.C. L.L. and F.C. conducted analysis of NSAID usage and incidence of Alzheimer's disease. F.O. J.A.K. and N.S.W. conducted diflunisal pharmacokinetic studies. M.E.F. and T.G. assisted in study of human postmortem brain tissue. V.E.W. assisted in analysis of human plasma samples. A.A.P. M.-K.S. E.V.-R. M.K.J. J.S.S. and J.D.R. wrote the manuscript. All authors reviewed and approved the manuscript. A.A.P. is an inventor on patents related to P7C3. L.G. is a founder of Aeton Therapeutics. No other authors declare competing interests. Funding Information: We thank those who provided blood and brain samples, Matthew N. Rasband for βIV-spectrin antibodies, Peter Davies for PHF1 (p-tau S396/S404) antibodies, Mikayla Huntley for tau seeding assay help, and Gloria Lee for providing brain tissue from tau knockout mice. Postmortem brain tissues were provided by the Neuropathology Core of Northwestern University ( NIH P30 AG013854 24 ). We thank the Translational Therapeutics Core of the Cleveland Alzheimer’s Disease Research Center ( NIH/NIA 1 P30 AGO62428-01 ) for assisting in the study with human postmortem brain tissues. The SV2 monoclonal antibody developed by K.M. Buckley was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH, and maintained at The University of Iowa, Department of Biology (Iowa City, IA). This work was supported by a grant to A.A.P. from the Brockman Foundation . A.A.P. was also supported by Elizabeth Ring Mather and William Gwinn Mather Fund , S. Livingston Samuel Mather Trust , G.R. Lincoln Family Foundation , Wick Foundation , the Leonard Krieger Fund of the Cleveland Foundation , Gordon and Evie Safran , and Louis Stokes VA Medical Center resources and facilities. Acknowledgment is made to the donors of Alzheimer’s Disease Research , a program of BrightFocus Foundation , for support of M.-K.S. in this research ( A2019551F ). A.A.P., M.K.J., J.D.R., and J.S.S. are supported by Project 19PABH134580006-AHA/Allen Initiative in Brain Health and Cognitive Impairment . E.V.-R. was supported by Free Radical and Radiation Biology, University of Iowa ( T32 CA078586 ). F.C. and A.A.P. are supported together by NIA/NIH ( RO1AG066707 ) and also the Translational Therapeutic Core of the Cleveland Alzheimer’s Disease Research Center ( NIH/NIA 1 P30 AGO62428-01 ), which assisted in the study of human postmortem brain tissue and longitudinal analysis of patient data. D.J.L. was supported by The Miami Project to Cure Paralysis and NIH/NINDS ( NS098740 ). S.J.F. and M.T.P. were supported by VA BLR&D MERIT Award ( 2 101 BXOO2439-04A1 ) and Research Career Scientist Awards from Department of Veterans Affairs , with resources of VA Western NY Healthcare System (Buffalo, NY), and Atlanta VA Medical Center (Decatur, GA). S.J.F. was supported by Clinical and Translational Science Award ( UL1TR001412 ) to University of Buffalo from National Center for Advancing Translational Sciences (NCATS/NIH). R.S.A. was supported by Career Development Award ( CDA-2 RX002928 ) from Department of Veterans Affairs . T.G. was supported by NIA/NIH ( RO1AG062566 ). M.E.F. was supported by NIA/NIH ( KO8AG065463 ). Publisher Copyright: © 2021

PY - 2021/5/13

Y1 - 2021/5/13

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - P7C3

KW - acetylation

KW - congenital muscular dystrophy

KW - diflunisal

KW - neurodegeneration

KW - neuroprotection

KW - omigapil

KW - salsalate

KW - tau

KW - traumatic brain injury

UR - http://www.scopus.com/inward/record.url?scp=85104992839&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85104992839&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.03.032

DO - 10.1016/j.cell.2021.03.032

M3 - Article

C2 - 33852912

AN - SCOPUS:85104992839

SN - 0092-8674

VL - 184

SP - 2715-2732.e23

JO - Cell

JF - Cell

IS - 10

ER -

Reducing acetylated tau is neuroprotective in brain injury

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ASJC Scopus subject areas

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