The acetylation of tau inhibits its function and promotes pathological tau aggregation
Open accessAbstract
The microtubule associated protein tau promotes neuronal survival through binding and stabilization of MTs. Phosphorylation regulates tau-microtubule interactions and hyperphosphorylation contributes to the aberrant formation of insoluble tau aggregates in Alzheimer's disease (AD) and related tauopathies. However, other pathogenic post-translational tau modifications have not been well characterized. Here we demonstrate that tau acetylation inhibits tau function via impaired tau-microtubule interactions and promotes pathological tau aggregation. Mass spectrometry analysis identified specific lysine residues, including lysine 280 (K280) within the microtubule-binding motif as the major sites of tau acetylation. Immunohistochemical and biochemical studies of brains from tau transgenic mice and patients with AD and related tauopathies showed that acetylated tau pathology is specifically associated with insoluble, Thioflavin-positive tau aggregates. Thus, tau K280 acetylation in our studies was only detected in diseased tissue, suggesting it may have a role in pathological tau transformation. This study suggests that tau K280 acetylation is a potential target for drug discovery and biomarker development for AD and related tauopathies.
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Increased expression of HDAC6 decreases Tau acetylation, a key factor contributing to the formation of Tau aggregates.
“Increased expression of HDAC6 decreases Tau acetylation [40], which is a key factor contributing to the formation of Tau aggregates [39, 49].”
From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [40]
Lys280 acetylation enhances fibrillization, whereas Lys274 and Lys281 acetylation promotes tau distribution to the soma and dendrites, resulting in synaptic and cognitive dysfunction.
“Lys280 acetylation enhances fibrillization, whereas Lys274 and Lys281 acetylation promotes tau distribution to the soma and dendrites, and resulting in synaptic and cognitive dysfunction [157, 158, 160].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [158]
Tau acetylation at Lys280 can only be detected in AD and 4R tauopathies such as corticobasal degeneration and PSP.
“Acetylation of tau at Lys174, Lys274, Lys280, and Lys281 have been well characterized due to their association with AD: tau acetylation at Lys280 can only be detected in AD and 4R tauopathies such as corticobasal degeneration and PSP.”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [158]
Acetylation of tau at Lys274, Lys280, and Lys281 residues within the microtubule binding domain impairs tau binding to microtubules.
“Specifically, acetylation of tau at Lys274, Lys280 and Lys281 residues within the microtubule binding domain impairs tau binding to microtubules.”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [158]
Increased levels of acetylated tau at Lys174, Lys274, and Lys281 have been observed in the brain of AD patients at varying disease stages.
“Additionally, increased levels of acetylated tau at Lys174, Lys 274, and Lys281 have been observed in the brain of AD patients at varying disease stages [156–159].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [158]
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].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [47]
Tau is a substrate of HDAC6, and inhibition of HDAC6 increases tau acetylation.
“Cohen et al. reported that tau is a substrate of HDAC6, and the inhibition of HDAC6 increases tau acetylation [47].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [47]
Acetylation of tau inhibits its function and promotes pathological aggregation.
“Acetylation of tau inhibits its function and promotes pathological aggregation.373–375”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [375]
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- Authors
- Cohen, T. J., Guo, J. L., Hurtado, D. E., Kwong, L. K., Mills, I. P., Trojanowski, J. Q., & Lee, V. M. Y.
- Affiliations
- University of Pennsylvania (US)
- University of Pennsylvania Health System (US)
- Corresponding author
- Lee, Virginia M. Y.
- Venue
- Nature Communications
- Published
- 2011-03-22
- Volume
- 2
- Issue
- 1
- Pages
- 252-252
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3120096
- OpenAlex
- W2048332130
- Cited by
- 724
- References
- 29
- Citations by year
- 2026: 46 · 2025: 49 · 2024: 49 · 2023: 55 · 2022: 56 · 2021: 72 · 2020: 64 · 2019: 42 · 2018: 62 · 2017: 41 · 2016: 41 · 2015: 43 · 2014: 33 · 2013: 37 · 2012: 23
- FWCI
- 22.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (AG-010124, P30AG010124, P01AG017586, AG17586)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau acetylation, tau protein, tau aggregation, Alzheimer's disease, tauopathy, post-translational modification, microtubule stabilization, biomarkers, therapeutic target
- MeSH terms
- Acetylation, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Female, Humans, Immunohistochemistry, Lysine, Male, Membrane Proteins, Mice, Transgenic, Microtomy, Microtubules, Middle Aged, Neurons, Phosphorylation, Protein Binding, Protein Processing, Post-Translational, Recombinant Proteins, Mass Spectrometry, Transfection, tau Proteins, Mice, HEK293 Cells
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