Intranasal Paclitaxel Alters Alzheimer's Disease Phenotypic Features in 3xTg-AD Mice
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| Authors: | Cross, DJ; Huber, BR; Silverman, MA; Cline, MM; Gill, TB; Cross, CG; Cook, DG; Minoshima, S |
| Year: | 2021 |
| Journal: | J. Alzheimers Dis. 83: 379-394 Article Link (DOI) PubMed |
| Title: | Intranasal Paclitaxel Alters Alzheimer's Disease Phenotypic Features in 3xTg-AD Mice |
| Abstract: | Background: Microtubule stabilizing drugs, commonly used as anti-cancer therapeutics, have been proposed for treatment of Alzheimer's disease (AD); however, many do not cross the blood-brain barrier. Objective: This research investigated if paclitaxel (PTX) delivered via the intranasal (IN) route could alter the phenotypic progression of AD in 3xTg-AD mice. Methods: We administered intranasal PTX in 3XTg-AD mice (3xTg-AD n = 15, 10 weeks and n = 10, 44 weeks, PTX: 0.6 mg/kg or 0.9%saline (SAL)) at 2-week intervals. After treatment, 3XTg-AD mice underwent manganese-enhanced magnetic resonance imaging to measure in vivo axonal transport. In a separate 3XTg-AD cohort, PTX-treated mice were tested in a radial water tread maze at 52 weeks of age after four treatments, and at 72 weeks of age, anxiety was assessed by an elevated-plus maze after 14 total treatments. Results: PTX increased axonal transport rates in treated 3XTg-AD compared to controls (p <= 0.003). Further investigation using an in vitro neuron model of A beta-induced axonal transport disruption confirmed PTX prevented axonal transport deficits. Confocal microscopy after treatment found fewer phospho-tau containing neurons (5.25 +/- 3.8 versus 8.33 +/- 2.5, p < 0.04) in the CA1, altered microglia, and reduced reactive astrocytes. PTX improved performance of 3xTg-AD on the water tread maze compared to controls and not significantly different from WT (Day 5, 143.8 +/- 43 versus 91.5 +/- 77s and Day 12, 138.3 +/- 52 versus 107.7 +/- 75s for SAL versus PTX). Elevated plus maze revealed that PTX-treated 3xTg-AD mice spent more time exploring open arms (Open arm 129.1 +/- 80 versus 20.9 +/- 31s for PTX versus SAL, p <= 0.05). Conclusion: Taken collectively, these findings indicate that intranasal-administered microtubule-stabilizing drugs may offer a potential therapeutic option for treating AD. |
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