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Updated: Aug 7, 2026
An In Vitro Model for Studying Tau Aggregation Using Lentiviral-mediated Transduction of Human Neurons
Published on: May 23, 2019
Ongoing in vivo studies with cytoskeletal drugs in tau transgenic mice
Mary L Michaelis1, G Georg, H Telikepalli
1Department of Pharmacology & Toxicology, School of Pharmacy, University of Kansas, 1241 Wescoe Hall Dr., Lawrence, KS 66045, USA. mlm@ku.edu
Abstract:
Most drug discovery efforts for Alzheimer's disease (AD) have focused on prevention or clearance of beta-amyloid (Abeta) fibrils or oligomers, with far less attention to prevention of tau abnormalities that lead to neurofibrillary tangles (NFTs). Much evidence now indicates that Abeta multimers can trigger neurodegenerative changes that involve formation of dystrophic neurites and cytoskeletal collapse, possibly due loss of microtubule (MT) stabilization by the tau protein. We have found that several MT-stabilizing agents such as Taxol significantly enhanced neuronal survival in the presence of Abeta and identified agents that enter the brain, a necessity for in vivo testing in animal models of tau pathology. Studies were designed to test two agents in the tau mutant (JNPL3) mouse that develops severe motor deficits at about seven months of age, accompanied by neuropathological markers of tau pathology. In addition to using motor performance tests through the planned period of drug administration, we designed a simple appetitive memory test that required a reduction in ad lib food intake. Although the neurochemical data are still being analyzed, we were surprised to find that all of the JNPL3 mice, whether receiving the drug or not, developed no signs of motor impairment up to 10 months of age. This is considerably beyond the age at which free-fed mice survived and suggests that the food restriction alone may have delayed the pathological process. A study is ongoing with free-fed mice to determine if the drug interventions do have any beneficial effects in these mutant mice.
Insights
This study explored tau pathology in Alzheimer's disease (AD) models. Unexpectedly, food restriction in mice delayed motor deficits, suggesting a novel therapeutic avenue beyond amyloid-beta targeting.
Area of Science:
- Neuroscience
- Pharmacology
- Gerontology
Background:
- Alzheimer's disease (AD) research primarily targets beta-amyloid (Abeta), neglecting tau pathology and neurofibrillary tangles (NFTs).
- Abeta multimers may induce neurodegeneration by disrupting microtubule (MT) stabilization, impacting neuronal function.
- MT-stabilizing agents show potential for enhancing neuronal survival against Abeta toxicity.
Purpose of the Study:
- To investigate the efficacy of brain-penetrant MT-stabilizing agents in a mouse model of tau pathology.
- To evaluate the impact of these agents on motor deficits and cognitive function in the JNPL3 mouse model.
- To explore potential synergistic effects of drug treatment and dietary interventions on tau-related neurodegeneration.
Main Methods:
- Utilized the JNPL3 mouse model, which exhibits motor deficits and tau pathology.
- Administered two MT-stabilizing agents designed for brain penetration.
- Assessed motor performance and implemented an appetitive memory test requiring reduced food intake.
Main Results:
- Unexpectedly, all JNPL3 mice, regardless of treatment, showed no motor impairment up to 10 months of age.
- This delayed pathology onset extended beyond the typical survival age for free-fed mice.
- Preliminary findings suggest food restriction may independently delay tau-related pathological processes.
Conclusions:
- Food restriction appears to be a significant factor in delaying motor deficits in the JNPL3 mouse model.
- Further studies are needed to elucidate the precise mechanisms of food restriction's protective effects.
- Ongoing research will determine if drug interventions offer additional benefits in free-fed conditions.
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