Cited by 404Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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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

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Zhang, Bin, Carroll, Jenna, Trojanowski, John Q., Yao, Yuemang, Iba, Michiyo, Potuzak, Justin S., Hogan, Anne-Marie L., Xie, Sharon X., Ballatore, Carlo, Smith, Amos B., Lee, Virginia M.-Y., Brunden, Kurt R.·2012·The Journal of Neuroscience

DOI 10.1523/jneurosci.4922-11.2012PMC PMC3321513

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Abstract

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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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: Zhang, Bin
Trojanowski, John Q.
Iba, Michiyo
Xie, Sharon X.
Ballatore, Carlo
Smith, Amos B.
Lee, Virginia M.-Y.
Brunden, Kurt R.
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
DOI: 10.1523/jneurosci.4922-11.2012
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: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 184 d)
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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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

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