Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice
Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice
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DOI：
10.1016/j.expneurol.2007.01.037
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发表时间：
2007-05-01
影响因子：
5.3
通讯作者：
Mattson, Mark P.
中科院分区：
文献类型：
--
作者：
Nelson, Rhonda L.;Guo, Zhihong;Mattson, Mark P.
抑郁史是阿尔茨海默病（AD）的一个危险因素，这表明预防性服用抗抑郁药可能会延缓疾病进程并保持认知功能。本研究发现，在3xTgAD AD小鼠模型中，抗抑郁药帕罗西汀的症状前治疗可减轻疾病进程并改善认知能力。5个月大的雄性和雌性3xTgAD和非转基因小鼠每天给予帕罗西汀或生理盐水，持续5个月。对7个月大的小鼠进行野外活动测试，并在10个月时评估被动回避和莫里斯游泳任务的表现。与非转基因小鼠相比，3xTgAD小鼠在被动回避测试中表现出探索性活动降低，转移延迟增加，Morris空间导航任务表现受损。帕罗西汀治疗改善了3xTgAD雄性和雌性小鼠的空间导航缺陷，但不影响游泳速度或行进距离，表明保留了认知功能。与盐水处理的3xTgAD小鼠相比，帕罗西汀处理的雄性和雌性3xTgAD小鼠海马中淀粉样蛋白β肽（A β）水平和A β免疫反应神经元数量显著降低。与雄性3xTgAD小鼠相比，雌性3xTgAD小鼠海马和杏仁核的tau病理明显减少，帕罗西汀减轻了雄性3xTgAD小鼠的tau病理。在小鼠模型中，一种安全有效的抗抑郁药能够抑制神经病理变化并改善认知能力，这表明预防性使用这种药物可能会延缓人类AD的发展。(C) 2007爱思唯尔公司版权所有。
A history of depression is a risk factor for Alzheimer's disease (AD), suggesting the possibility that antidepressants administered prophylactically might retard the disease process and preserve cognitive function. Here we report that pre-symptomatic treatment with the antidepressant paroxetine attenuates the disease process and improves cognitive performance in the 3xTgAD mouse model of AD. Five-month-old mate and female 3xTgAD and non-transgenic mice were administered either paroxetine or saline daily for 5 months. Open-field activity was tested in 7-month-old mice and performance in passive avoidance and Morris swim tasks were evaluated at 10 months. 3xTgAD mice exhibited reduced exploratory activity, increased transfer latency in the passive avoidance test and impaired performance in the Morris spatial navigation task compared to nontransgenic control mice. Paroxetine treatment ameliorated the spatial navigation deficit in 3xTgAD male and female mice, without affecting swim speed or distance traveled, suggesting a preservation of cognitive function. Levels of amyloid beta-peptide (A beta) and numbers of A beta immunoreactive neurons were significantly reduced in the hippocampus of male and female paroxetine-treated 3xTgAD mice compared to saline-treated 3xTgAD mice. Female 3xTgAD mice exhibited significantly less tau pathology in the hippocampus and amygdala compared to male 3xTgAD mice, and paroxetine lessened tau pathology in male 3xTgAD mice. The ability of a safe and effective antidepressant to suppress neuropathological changes and improve cognitive performance in a mouse model suggests that such drugs administered prophylactically might retard the development of AD in humans. (C) 2007 Elsevier Inc. All rights reserved.