Epothilone D Improves Microtubule Density, Axonal Integrity, and Cognition in a Transgenic Mouse Model of Tauopathy
Open accessAbstract
Neurons in the brains of those with Alzheimer's disease (AD) and many frontotemporal dementias (FTDs) contain neurofibrillary tangles comprised of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs), and tau misfolding could lead to a loss of this function with consequent MT destabilization and neuronal dysfunction. Accordingly, a possible therapeutic strategy for AD and related “tauopathies” is treatment with a MT-stabilizing anti-cancer drug such as paclitaxel. However, paclitaxel and related taxanes have poor blood–brain barrier permeability and thus are unsuitable for diseases of the brain. We demonstrate here that the MT-stabilizing agent, epothilone D (EpoD), is brain-penetrant and we subsequently evaluated whether EpoD can compensate for tau loss-of-function in PS19 tau transgenic mice that develop forebrain tau inclusions, axonal degeneration and MT deficits. Treatment of 3-month-old male PS19 mice with low doses of EpoD once weekly for a 3 month period significantly improved CNS MT density and axonal integrity without inducing notable side-effects. Moreover, EpoD treatment reduced cognitive deficits that were observed in the PS19 mice. These results suggest that certain brain-penetrant MT-stabilizing agents might provide a viable therapeutic strategy for the treatment of AD and FTDs.
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Hyperphosphorylated tau becomes dissociated from microtubules, leading to impairment of axonal transport and appearance of dystrophic axons.
“Hyperphosphorylated tau becomes dissociated from microtubules, leading to impairment of axonal transport and appearance of dystrophic axons 8–11.”
From Amyloid-beta induced retrograde axonal degeneration in a mouse tauopathy model (2019) · cites this paper as [10]
The Introduction (page not indicated) describes reduced microtubule binding by hyperphosphorylated tau and says the resulting destabilization could impair axonal transport. The Results (page not indicated) report dystrophic axons in PS19 mice and call microtubule destabilization their likely cause. The claim presents this proposed causal chain as established, which the paper does not. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe data presented here provide further evidence that therapeutic approaches alternative to mitigating tau phosphorylation (such as improved microtubule stability) may be productive.
“the data presented here provide further evidence that such approaches may be productive”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [355]
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References 35 · Cited by 320
Research works printed but not linked: 27
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- Authors
- Brunden, K. R., Zhang, B., Carroll, J., Yao, Y., Potuzak, J. S., Hogan, A.-M. L., Iba, M., James, M. J., Xie, S. X., Ballatore, C., Smith, A. B., Lee, V. M.-Y., & Trojanowski, J. Q.
- 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
- 2010-10-13
- Volume
- 30
- Issue
- 41
- Pages
- 13861-13866
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2958430
- OpenAlex
- W2036878135
- Cited by
- 320
- References
- 35
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 17 · 2023: 9 · 2022: 24 · 2021: 16 · 2020: 25 · 2019: 15 · 2018: 26 · 2017: 21 · 2016: 30 · 2015: 21 · 2014: 29 · 2013: 14 · 2012: 24
- FWCI
- 11.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG 10 124, 5u01ag024904-10, NS53488, AG 17586, AG24904)
- National Institute on Aging (U01-AG-024904, AG 029213, P30AG010124, P01AG017586, AG17586, AG-10124, U01AG029213, AG24904, U19AG024904)
- National Institute of Neurological Disorders and Stroke (NS53488, P50NS053488)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- epothilone D, tauopathy, Alzheimer's disease, frontotemporal dementia, microtubule stabilization, tau hyperphosphorylation, neurofibrillary tangles, axonal integrity, cognitive impairment, brain-penetrant drugs, taxanes, axonal degeneration
- MeSH terms
- Animals, Axons, Brain, Cognition, Female, Male, Mice, Transgenic, Microscopy, Electron, Microtubules, Motor Skills, Neurons, Phosphorylation, Random Allocation, tau Proteins, Maze Learning, Tauopathies, Epothilones, Rotarod Performance Test, Tubulin Modulators, Mice
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