The DOI matches its Crossref record; 64 of the 64 references it cites were found in a registry or an index.
Reducing acetylated tau is neuroprotective in brain injury
Open accessAbstract
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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In the citing paper
“Beyond neurodegenerative and neurodevelopmental disorders, tau ablation has also been shown to improve outcomes in models of neurological injury and vascular stress, such TBI and high-salt diet-induced vascular dysfunction, with associated improvements in cognitive performance [72, 86, 87].”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [72]
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“In addition, the acetylation of tau is an early pathological feature of neurodegeneration. Acetylated tau inhibits its degradation, promotes pathological aggregation and propagation, and contributes to tauopathy [46–51].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [51]
In the citing paper
“Inhibiting p300 with salsalate, a non-steroidal anti-inflammatory drug, could induce tau deacetylation, preserve tau axonal localization, and protect mice from neurodegeneration [51].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [51]
In the citing paper
“Abnormal acetylation of tau on lysine residues spans the microtubule-binding repeat region (MTBR), and this modification alone is sufficient to induce tau pathology and neurodegeneration [51].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [51]
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Citations
Cites
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Acetylation of Tau Inhibits Its Degradation and Contributes to Tauopathy
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Self-citationS-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration
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The acetylation of tau inhibits its function and promotes pathological tau aggregation
Cohen, T. J., Guo, J. L., Hurtado, D. E., Kwong, L. K., Mills, I. P., Trojanowski, J. Q., & Lee, V. M. Y. (2011) · Nature Communications · doi:10.1038/ncomms1255 · Cited by 724
Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease
Wesseling, H., Mair, W., Kumar, M., Schlaffner, C. N., Tang, S., Beerepoot, P., Fatou, B., Guise, A. J., Cheng, L., Takeda, S., et al. (2020) · Cell · doi:10.1016/j.cell.2020.10.029 · Cited by 688
Neuron-Specific Enolase as a Biomarker: Biochemical and Clinical Aspects
Isgrò, M. A., Bottoni, P., & Scatena, R. (2015) · Advances in experimental medicine and biology · doi:10.1007/978-94-017-7215-0_9 · Cited by 600
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Modulation of cellular processes by histone and non-histone protein acetylation
Shvedunova, M., & Akhtar, A. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00441-y · Cited by 1,007
Neuroinflammation in Alzheimer disease
Heneka, M. T., van der Flier, W. M., Jessen, F., Hoozemanns, J., Thal, D. R., Boche, D., Brosseron, F., Teunissen, C., Zetterberg, H., Jacobs, A. H., et al. (2025) · Nature Reviews Immunology · doi:10.1038/s41577-024-01104-7 · Cited by 638
Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation
Chen, Y., & Yu, Y. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02853-3 · Cited by 516
Zhong, Q., Xiao, X., Qiu, Y., Xu, Z., Chen, C., Chong, B., Zhao, X., Hai, S., Li, S., An, Z., et al. (2023) · MedComm · doi:10.1002/mco2.261 · Cited by 442
Tau-targeting therapies for Alzheimer disease: Current status and future directions
Congdon, E. E., Ji, C., Tetlow, A. M., Jiang, Y., & Sigurdsson, E. M. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00883-2 · Cited by 371
Metadata
- Authors
- 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., Gan, L., Liebl, D. J., Savarraj, J. P. J., Torres, G. L., Ahnstedt, H., McCullough, L. D., Kitagawa, R. S., Choi, H. A., Zhang, P., Hou, Y., Chiang, C.-W., Li, L., Ortiz, F., Kilgore, J. A., Williams, N. S., Whitehair, V. C., Gefen, T., Flanagan, M. E., Stamler, J. S., Jain, M. K., Kraus, A., Cheng, F., Reynolds, J. D., & Pieper, A. A.
- Affiliations
- University Hospitals of Cleveland (US)
- University of Iowa (US)
- Georgia Institute of Technology (US)
- Buffalo VA Medical Center (US)
- Gladstone Institutes (US)
- Buck Institute for Research on Aging (US)
- Weill Cornell Medicine (US)
- University of Miami (US)
- The University of Texas Health Science Center at Houston (US)
- The Ohio State University (US)
- Cleveland Clinic (US)
- The University of Texas Southwestern Medical Center (US)
- MetroHealth (US)
- Northwestern University (US)
- Case Western Reserve University (US)
- Cornell University (US)
- Corresponding author
- Pieper, Andrew A.
- ORCID
- Shin, Min-Kyoo
- Koh, Yeojung
- Dhar, Matasha
- Chaubey, Kalyani
- Cintrón-Pérez, Coral J.
- Barker, Sarah
- Miller, Emiko
- Franke, Kathryn
- Noterman, Maria F.
- Seth, Divya
- Allen, Rachael S.
- Motz, Cara T.
- Rao, Sriganesh Ramachandra
- Skelton, Lara A.
- Pardue, Machelle T.
- Fliesler, Steven J.
- Wang, Chao
- Tracy, Tara E.
- Gan, Li
- Liebl, Daniel J.
- Savarraj, Jude P.J.
- Ahnstedt, Hilda
- McCullough, Louise D.
- Choi, H. Alex
- Zhang, Pengyue
- Chiang, Chien-Wei
- Li, Lang
- Kilgore, Jessica A.
- Williams, Noelle S.
- Whitehair, Victoria C.
- Gefen, Tamar
- Flanagan, Margaret E.
- Stamler, Jonathan S.
- Jain, Mukesh K.
- Kraus, Allison
- Cheng, Feixiong
- Reynolds, James D.
- Pieper, Andrew A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 184
- Issue
- 10
- Pages
- 2715-2732.e23
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8491234
- OpenAlex
- W3152963650
- Cited by
- 226
- References
- 64
- Citations by year
- 2026: 36 · 2025: 60 · 2024: 45 · 2023: 40 · 2022: 34 · 2021: 11
- FWCI
- 20.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX002439, IK2 RX002928)
- National Institutes of Health (5p30ag062428-02, UL1TR001412)
- National Institute on Aging (P30-AG062428, F32AG043301, R01AG066707, K01AG057862, R01AG062566, P30AG013854, K08AG065463)
- National Cancer Institute (P01CA217797, T32CA078586)
- National Institute of General Medical Sciences (T32GM007250)
- National Institute of Neurological Disorders and Stroke (R01NS098740)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- tau acetylation, traumatic brain injury, Alzheimer's disease, SIRT1, neurodegeneration, neurobehavioral impairment, blood biomarkers, salsalate, diflunisal, neuroprotection
- MeSH terms
- Neuroprotection, Brain Injuries, Traumatic, p300-CBP-Associated Factor, Acetylation, Alzheimer Disease, Animals, Anti-Inflammatory Agents, Non-Steroidal, Cell Line, Diflunisal, Female, Humans, Male, Mice, Inbred C57BL, Neurons, Salicylates, Biomarkers, tau Proteins, Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating), p300-CBP Transcription Factors, Mice, Sirtuin 1
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