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The Microtubule-Stabilizing Agent, Epothilone D, Reduces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, and Alzheimer-Like Pathology in an Interventional Study with Aged Tau Transgenic Mice
Open accessAbstract
Neurodegenerative tauopathies, such as Alzheimer's disease (AD), are characterized by insoluble deposits of hyperphosphorylated tau protein within brain neurons. Increased phosphorylation and decreased solubility has been proposed to diminish normal tau stabilization of microtubules (MTs), thereby leading to neuronal dysfunction. Earlier studies have provided evidence that small molecule MT-stabilizing drugs that are used in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been established whether treatment with a small molecule MT-stabilizing compound will provide benefit in a transgenic model with pre-existing tau pathology, as would be seen in human patients with clinical symptoms. Accordingly, we describe here an interventional study of the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), in aged PS19 mice with existing tau pathology and related behavioral deficits. EpoD treatment reduced axonal dystrophy and increased axonal MT density in the aged PS19 mice, which led to improved fast axonal transport and cognitive performance. Moreover, the EpoD-treated PS19 mice had less forebrain tau pathology and increased hippocampal neuronal integrity, with no dose-limiting side effects. These data reveal that brain-penetrant MT-stabilizing drugs hold promise for the treatment of AD and related tauopathies, and that EpoD could be a candidate for clinical testing.
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“Although tau aggregates are hallmarks of AD, several studies have suggested that oligomeric tau in soluble forms may be the most potent neurotoxic form 68–73.”
From Amyloid-beta induced retrograde axonal degeneration in a mouse tauopathy model (2019) · cites this paper as [73]
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Metadata
- Authors
- Zhang, B., Carroll, J., Trojanowski, J. Q., Yao, Y., Iba, M., Potuzak, J. S., Hogan, A.-M. L., Xie, S. X., Ballatore, C., Smith, A. B., Lee, V. M.-Y., & Brunden, K. R.
- Affiliations
- University of Pennsylvania (US)
- Institute on Aging (US)
- Corresponding author
- Brunden, Kurt R.
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-03-14
- Volume
- 32
- Issue
- 11
- Pages
- 3601-3611
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3321513
- OpenAlex
- W1969129718
- Cited by
- 401
- References
- 67
- Citations by year
- 2026: 18 · 2025: 19 · 2024: 22 · 2023: 11 · 2022: 31 · 2021: 36 · 2020: 37 · 2019: 24 · 2018: 27 · 2017: 28 · 2016: 44 · 2015: 26 · 2014: 40 · 2013: 23 · 2012: 14
- FWCI
- 22.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bristol-Myers Squibb
- University of Pennsylvania
- National Institutes of Health
- National Institute on Aging (U01AG029213)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- epothilone D, microtubule stabilization, tauopathy, Alzheimer's disease, tau phosphorylation, axonal dystrophy, axonal transport, cognitive impairment, hippocampal neurons, PS19 mice, neuroprotection, drug repurposing
- MeSH terms
- Aging, Alzheimer Disease, Animals, Axons, Cognition Disorders, Humans, Male, Mice, Transgenic, Microtubules, tau Proteins, Neurotoxicity Syndromes, Tauopathies, Epothilones, Tubulin Modulators, Mice
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