Protopanaxadiol derivative DDPU improves behavior and cognitive deficit in AD mice involving regulation of both ER stress and autophagy
Protopanaxadiol derivative DDPU improves behavior and cognitive deficit in AD mice involving regulation of both ER stress and autophagy
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原人参二醇衍生物 DDPU 可改善 AD 小鼠的行为和认知缺陷，涉及内质网应激和自噬的调节
DOI：
10.1016/j.neuropharm.2017.11.033
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发表时间：
2018-03-01
影响因子：
4.7
通讯作者：
Shen, Xu
中科院分区：
文献类型：
--
作者：
Guo, Xiaodan;Lv, Jianlu;Shen, Xu
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其典型特征是β淀粉样蛋白（a β）斑块积累、神经原纤维缠结（NFT）形成和神经元死亡延长。侵袭性A β积累促进老年斑形成，扰乱内质网（ER）功能，触发未折叠蛋白反应（UPR），导致神经元凋亡。蛋白激酶rna样内质网激酶（PERK）的胁迫依赖性激活增加了真核翻译起始因子-2 α (eIF2 α)的磷酸化，进而促进β位点APP裂解酶1 （BACE1）的优先合成和A β的生成。此外，据报道，自噬功能障碍可导致包括AD在内的几种神经退行性疾病，自噬介导途径的损伤可能会构成性地刺激AD中A β的产生。本研究发现原嘌呤二醇衍生物1-（3,4-二甲氧基苯基）-3-（3-去羟基-20(s)-原嘌呤二醇-3 β -基）-尿素（DDPU）可有效改善APP/PS1转基因小鼠的日常生活活性（ADL）和认知缺陷。利用DDPU作为探针，深入研究了A β和内质网应力之间的串扰。DDPU主要通过抑制PERK/eIF2 α信号介导的BACE1翻译来减少A β的产生，并作为PI3K抑制剂通过PI3K/AKT/mTOR信号通路促进自噬来刺激A β的清除，同时表现出衰减内质网应激的神经保护作用。DDPU可能是首次报道的具有促进自噬和改善内质网应激双重作用的人参皂苷衍生物。我们的结果强调了DDPU在治疗AD方面的潜力。(C) 2017 Elsevier Ltd.版权所有。
Alzheimer's disease (AD) is a progressively neurodegenerative disease with typical hallmarks of amyloid beta (A beta) plaque accumulation, neurofibrillary tangle (NFT) formation and neuronal death extension. Aggressive A beta accumulation promotes senile plaque formation and perturbs endoplasmic reticulum (ER) function to trigger the unfolded protein response (UPR) leading to neuronal apoptosis. The stress dependent activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) increases the phosphorylation of eukaryotic translation initiation factor-2 alpha (eIF2 alpha) to promote the preferential synthesis of beta-site APP cleavage enzyme 1 (BACE1) and A beta generation in turn. Additionally, dysfunction in autophagy has been reported to contribute to several neurodegenerative diseases including AD, and impairment in autophagy-mediated pathway may constitutively stimulate the generation of A beta in AD. Here we discovered that protopanaxadiol derivative 1-(3,4-dimethoxyphenethyl)-3-(3-dehydroxyl-20(s)-protopanaxadiol-3 beta-yl)-urea (DDPU) effectively improved the activity of daily living (ADL) and cognitive deficits in APP/PS1 transgenic mice. The crosstalk between A beta and ER stress has been intensively investigated by using DDPU as a probe. DDPU reduced A beta production mainly by inhibiting the PERK/eIF2 alpha signaling-mediated BACE1 translation and stimulated A beta clearance by promoting autophagy as a PI3K inhibitor through PI3K/AKT/mTOR signaling pathway, while exhibited neuroprotective effect involving attenuation of ER stress. DDPU might be the first reported ginsenoside derivative with dual effects on both autophagy promotion and ER stress amelioration. Our results have highlighted the potential of DDPU in the treatment of AD. (C) 2017 Elsevier Ltd. All rights reserved.