Intranasal Paclitaxel Alters Alzheimer’s Disease Phenotypic Features in 3xTg-AD Mice

Article type: Research Article

Authors: Cross, Donna J.^{a; *} | Huber, Bertrand R.^{b; c} | Silverman, Michael A.^{d; e} | Cline, Marcella M.^{f; g} | Gill, Trevor B.^d | Cross, Chloe G.^a | Cook, David G.^{f; g} | Minoshima, Satoshi^a

Affiliations: [a] Department of Radiology and Imaging Sciences>, University of Utah, Salt Lake City, UT, USA | [b] Boston University Alzheimer’s Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA | [c] Department of Neurology, Boston University School of Medicine, Boston, MA, USA | [d] Department of Biological Sciences, Simon Fraser University, Burnaby, BC, Canada | [e] Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, BC, Canada | [f] The Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA | [g] Departments of Medicine, Pharmacology, Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA, USA

Correspondence: [*] Correspondence to: Donna J. Cross, PhD, University of Utah, Department of Radiology and Imaging Sciences, 30 N. 1900 E. #1A71, Salt Lake City, UT 84132-2140, USA. Tel.: +1 801 585 1346; E-mail: [email protected].

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 Aβ-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.

Keywords: Alzheimer’s disease, axonal transport, cognitive impairment, intranasal drug administration, microtubule stabilization

DOI: 10.3233/JAD-210109

Journal: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 379-394, 2021