Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Gerontology
• Pharmacology

Background:

• Cellular senescence, driven by tau protein accumulation, is implicated in Alzheimer's disease (AD).
• Previous studies showed senolytic therapy (dasatinib plus quercetin, DQ) reduced brain pathology and improved function in tau transgenic mice.
• DQ is currently in clinical AD trials, prompting comparison with fisetin (FIS), a senolytic with a potentially better side-effect profile.

Purpose of the Study:

• To directly compare the efficacy of DQ and FIS as senolytic therapies in a mouse model of Alzheimer's disease.
• To assess the impact of these senolytics on physical and cognitive functions, as well as neurodegeneration markers.

Main Methods:

• Fourteen-month-old wild type (WT) and tau transgenic (rTg4510) mice received 12 weeks of DQ, FIS, or vehicle via oral gavage.
• Physical and cognitive functions were assessed using frailty, Y-Maze, nest building, and grip duration tests.
• RNA sequencing was performed on brain tissue to analyze gene expression changes.

Main Results:

• Both DQ and FIS significantly increased frailty in rTg4510 mice.
• No significant effects on working memory or nest building were observed in rTg4510 mice.
• FIS showed neuroprotective effects against ventricular enlargement in female rTg4510 mice, while both senolytics induced subtle functional changes in WT mice.

Conclusions:

• Senolytic treatment did not significantly alter physical or cognitive outcomes in the advanced rTg4510 mouse model, suggesting the model may have been too advanced for intervention.
• Subtle functional changes in WT mice and gene expression data indicate a need for further research on senolytic selection, dosage, and treatment timing for AD.
• These findings underscore the complexity of senolytic therapy application in Alzheimer's disease research.