Department of Radiology and Imaging Sciences>, University of Utah, Salt Lake City, UT, USA.
Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA.
J Alzheimers Dis. 2021;83(1):379-394. doi: 10.3233/JAD-210109.
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.
This research investigated if paclitaxel (PTX) delivered via the intranasal (IN) route could alter the phenotypic progression of AD in 3xTg-AD mice.
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.
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).
Taken collectively, these findings indicate that intranasal-administered microtubule-stabilizing drugs may offer a potential therapeutic option for treating AD.
微管稳定剂药物通常被用作抗癌治疗药物，已被提议用于治疗阿尔茨海默病（AD）；然而，许多药物无法穿过血脑屏障。
本研究旨在探讨紫杉醇（PTX）经鼻内（IN）途径给药是否可以改变 3xTg-AD 小鼠的 AD 表型进展。
我们以 2 周的间隔时间向 3xTg-AD 小鼠（3xTg-AD n=15，10 周和 n=10，44 周，PTX：0.6 mg/kg 或 0.9%生理盐水（SAL））经鼻内给予紫杉醇。治疗后，3xTg-AD 小鼠接受锰增强磁共振成像以测量体内轴突运输。在另一组 3xTg-AD 小鼠中，在经过 4 次治疗后，在 52 周龄时，经紫杉醇治疗的小鼠在放射状水迷宫中进行测试，在 72 周龄时，在经过 14 次总治疗后，通过高架十字迷宫评估焦虑。
与对照组相比，PTX 增加了治疗的 3xTg-AD 中的轴突运输速率（p≤0.003）。使用 Aβ诱导的轴突运输障碍的体外神经元模型进行的进一步研究证实，PTX 可预防轴突运输缺陷。治疗后的共聚焦显微镜检查发现 CA1 中含有磷酸化 tau 的神经元数量减少（5.25±3.8 与 8.33±2.5，p<0.04），微胶质细胞改变，以及反应性星形胶质细胞减少。与对照组相比，PTX 改善了 3xTg-AD 在水迷宫上的表现，且与 WT 无显著差异（第 5 天，143.8±43 与 91.5±77s，第 12 天，138.3±52 与 107.7±75s 用于 SAL 与 PTX）。高架十字迷宫显示，PTX 治疗的 3xTg-AD 小鼠在开放臂上花费的时间更多（开放臂 129.1±80 与 20.9±31s 用于 PTX 与 SAL，p≤0.05）。
综上所述，这些发现表明，经鼻内给予的微管稳定剂药物可能为治疗 AD 提供一种潜在的治疗选择。
