Yang Yang, Wang Zhiyong, Cao Yu, Liu Jiangang, Li Peng, Li Hao, Liu Meixia
Institute of Geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Beijing Key Laboratory of Pharmacology of Chinese Materia Region, Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Front Pharmacol. 2019 Sep 17;10:1041. doi: 10.3389/fphar.2019.01041. eCollection 2019.
Alzheimer's disease (AD) is the most common type of dementia worldwide. The deposition of amyloid β (Aβ) is one of the most important pathological changes in AD. Autophagy, which mediates degradation of toxic proteins and maintains normal neuronal function, is dysfunctional in AD; dysfunctional autophagy is believed to be a critical pathological feature of AD. Here, we evaluated the and effects of a traditional Chinese medicinal formula called Yizhiqingxin formula (YQF) on autophagy. We determined that treatment with a high dose of YQF improved spatial memory and decreased the hippocampal Aβ burden in mice, an early onset AD model. Transmission electron microscopy and immunohistochemical data revealed that YQF enhanced autophagosome formation and also increased the levels of LC3II/LC3I and Beclin1. Further, we found that YQF treatment promoted autophagic activity by inhibiting the phosphorylation of the Mammalian target of rapamycin (mTOR) at the Ser2448 site. Moreover, the level of 4EBP1 increased after YQF intervention, indicating a suppression of mTOR signaling. YQF was also found to promote autophagosome degradation, as indicated by the decreased p62 levels and increased cathepsin D and V-ATPase levels. Taken together, YQF could improve spatial learning in / mice and ameliorate the accumulation of Aβ while promoting autophagy mTOR pathway modulation.
阿尔茨海默病（AD）是全球最常见的痴呆类型。淀粉样β蛋白（Aβ）沉积是AD最重要的病理变化之一。自噬介导有毒蛋白质的降解并维持神经元正常功能，在AD中功能失调；自噬功能失调被认为是AD的关键病理特征。在此，我们评估了一种名为益智清心方（YQF）的中药配方对自噬的影响。我们确定，高剂量YQF治疗可改善早发性AD模型APP/PS1小鼠的空间记忆并减轻海马区Aβ负担。透射电子显微镜和免疫组化数据显示，YQF增强自噬体形成，还增加了LC3II/LC3I和Beclin1的水平。此外，我们发现YQF治疗通过抑制雷帕霉素靶蛋白（mTOR）在Ser2448位点的磷酸化来促进自噬活性。而且，YQF干预后4EBP1水平升高，表明mTOR信号受到抑制。YQF还被发现可促进自噬体降解，表现为p62水平降低以及组织蛋白酶D和V-ATP酶水平升高。综上所述，YQF可改善APP/PS1小鼠的空间学习能力，减轻Aβ积累，同时通过调节mTOR途径促进自噬。
