Cited by 229Alzheimer's disease research and treatmentsTraumatic Brain Injury ResearchTraumatic Brain Injury and Neurovascular Disturbances

Reducing acetylated tau is neuroprotective in brain injury

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Shin, Min-Kyoo, Vázquez-Rosa, Edwin, Koh, Yeojung, Dhar, Matasha, Chaubey, Kalyani, Cintrón-Pérez, Coral J., Barker, Sarah, Miller, Emiko +35 more·2021·Cell

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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Crossref · 10.1016/j.cell.2021.03.032

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  • Tau ablation improves outcomes in models of TBI and high-salt diet-induced vascular dysfunction, with improvements in cognitive performance.

    “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]

    The Results section on p300/CBP inhibition reports that reducing acetylated tau after TBI protected mice from learning and memory deficits. It says this treatment did not change total tau, so it does not establish an effect of tau ablation. No passage found on high-salt diet-induced vascular dysfunction (searched: high-salt diet, vascular dysfunction, tau ablation); the indexed passages have no page numbers. (LLM, conf=0.86)

    Experimental — accuracy not yet measured
  • Acetylation of tau is an early pathological feature of neurodegeneration; acetylated tau inhibits its degradation, promotes pathological aggregation and propagation, and contributes to tauopathy.

    “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].”
  • Inhibiting p300 with salsalate induces tau deacetylation, preserves tau axonal localization, and protects mice from neurodegeneration.

    “Inhibiting p300 with salsalate, a non-steroidal anti-inflammatory drug, could induce tau deacetylation, preserve tau axonal localization, and protect mice from neurodegeneration [51].”
  • 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.

    “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].”

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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.
Venue
Cell
Publisher
Elsevier BV
Published
2021-05
Volume
184
Issue
10
Pages
2715-2732.e23
ISSN
0092-8674 (ISSN-L)
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
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
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Health Sciences › Medicine › 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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