Inhibiting A beta toxicity in Alzheimer's disease by a pyridine amine derivative
Inhibiting A beta toxicity in Alzheimer's disease by a pyridine amine derivative
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吡啶胺衍生物抑制阿尔茨海默病中的 Aβ 毒性
DOI：
10.1016/j.ejmech.2019.02.052
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发表时间：
2019
影响因子：
6.7
通讯作者：
Wang Xiaoyong
中科院分区：
文献类型：
--
作者：
Zhu Zhenzhu;Yang Tao;Zhang Lei;Liu Lulu;Yin Enmao;Zhang Changli;Guo Zijian;Xu Chen;Wang Xiaoyong
阿尔茨海默病（Alzheimer's disease，AD）是一种神经退行性疾病，目前尚无根治性治疗方法。多种因素诱导的淀粉样β肽（Aβ）聚集与AD的发病有关。合成了一种吡啶胺衍生物3-二（吡啶-2-基甲基）氨甲基-5-羟基苄基三苯基溴化鏻（PAT）。PAT对自身和金属诱导的Aβ聚集的抑制作用通过硫磺素T荧光、圆二色谱和TEM证实。Western blot、RT-PCR和荧光成像结果表明，PAT能减轻Aβ诱导的线粒体瘫痪，减少ROS的产生，保护线粒体功能。遗传分析表明，热休克蛋白参与减轻Aβ毒性。PAT还抑制线虫乙酰胆碱酯酶的活性。Morris水迷宫实验表明，PAT能显著改善APP/PS1 AD模型小鼠的记忆和认知能力。体外和体内研究均表明，PAT能有效对抗Aβ的毒性，改善AD小鼠的认知功能，有望成为抗AD药物的先导化合物。
Alzheimer's disease (AD) is a neurodegenerative disorder with no radical therapy. Aggregation of amyloidβ-peptide (Aβ) induced by various factors is associated with pathogenesis of AD. A pyridine amine derivative, 3-bis(pyridin-2-ylmethyl)aminomethyl-5-hydroxybenzyltriphenylphosphonium bromide (PAT), is synthesized. The inhibition of self- and metal-induced Aβaggregation by PAT is confirmed by thioflavine T fluorescence, circular dichroism spectroscopy, and TEM. Western blot, RT-PCR and fluorescence imaging indicate that PAT can alleviate the Aβ-induced paralysis, reduce the production of ROS, and protect the mitochondrial function in transgenicC. elegans. Genetic analyses indicate that heat shock protein is involved in the alleviation of Aβtoxicity. PAT also inhibits the activity of acetylcholinesterase inC. elegans. Morris water maze test shows that the memory and cognitive ability of APP/PS1 AD model mice are significantly improved by PAT. Bothin vitroandin vivostudies demonstrate that PAT is effective in counteracting Aβtoxicity and ameliorating cognitive functions in AD mice, and therefore a potential lead compound of anti-AD drugs.