Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies
Open accessAbstract
The microtubule-binding protein, tau, is the major component of neurofibrillary inclusions characteristic of Alzheimer's disease and related neurodegenerative tauopathies. When tau fibrillizes, it undergoes abnormal post-translational modifications resulting in decreased solubility and altered microtubule-stabilizing properties. Recently, we reported that the abnormal acetylation of tau at lysine residue 280 is a novel, pathological post-translational modification. Here, we performed detailed immunohistochemistry to further examine acetylated-tau expression in Alzheimer's disease and other major tauopathies. Immunohistochemistry using a polyclonal antibody specific for acetylated-tau at lysine 280 was conducted on 30 post-mortem central nervous system regions from patients with Alzheimer's disease (10 patients), corticobasal degeneration (5 patients), and progressive supranuclear palsy (5 patients). Acetylated-tau pathology was compared with the sequential emergence of other tau modifications in the Alzheimer's disease hippocampus using monoclonal antibodies to multiple well-characterized tau epitopes. All cases studied showed significant acetylated-tau pathology in a distribution pattern similar to hyperphosphorylated-tau. Acetylated-tau pathology was largely in intracellular, thioflavin-S-positive tau inclusions in Alzheimer's disease, and also thioflavin-S-negative pathology in corticobasal degeneration and progressive supranuclear palsy. Acetylated-tau was present throughout all stages of Alzheimer's disease pathology, but was more prominently associated with pathological tau epitopes in moderate to severe-stage cases. These temporal and morphological immunohistochemical features suggest acetylation of tau at this epitope is preceded by early modifications, including phosphorylation, and followed by later truncation events and cell death in Alzheimer's disease. Acetylation of tau at lysine 280 is a pathological modification that may contribute to tau-mediated neurodegeneration by both augmenting losses of normal tau properties (reduced solubility and microtubule assembly) as well as toxic gains of function (increased tau fibrillization). Thus, inhibiting tau acetylation could be a disease-modifying target for drug discovery target in tauopathies.
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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 [159]
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 [159]
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- Authors
- Irwin, D. J., Cohen, T. J., Grossman, M., Arnold, S. E., Xie, S. X., Lee, V. M.-Y., & Trojanowski, J. Q.
- Affiliations
- University of Pennsylvania (US)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-02-24
- Volume
- 135
- Issue
- 3
- Pages
- 807-818
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC3286338
- OpenAlex
- W2149168676
- Cited by
- 281
- References
- 49
- Citations by year
- 2026: 15 · 2025: 17 · 2024: 13 · 2023: 23 · 2022: 24 · 2021: 26 · 2020: 24 · 2019: 14 · 2018: 19 · 2017: 23 · 2016: 17 · 2015: 16 · 2014: 22 · 2013: 21 · 2012: 7
- FWCI
- 14.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P30AG010124, T32AG000255)
- 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, Alzheimer's disease, tauopathy, corticobasal degeneration, progressive supranuclear palsy, neurofibrillary tangles, tau phosphorylation, tau fibrillization, tau truncation, thioflavin S, microtubule-binding protein
- MeSH terms
- Acetylation, Aged, Alzheimer Disease, Epitopes, Basal Ganglia, Cerebral Cortex, Female, Humans, Immunohistochemistry, Male, Middle Aged, Nerve Degeneration, Phosphorylation, Supranuclear Palsy, Progressive, Tissue Banks, Neurofibrillary Tangles, tau Proteins, Disease Progression, Tauopathies, Proteostasis Deficiencies
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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