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A Novel Compound YS-5-23 Exhibits Neuroprotective Effect by Reducing β-Site Amyloid Precursor Protein Cleaving Enzyme 1's Expression and H2O2-Induced Cytotoxicity in SH-SY5Y Cells.
Neurochemical Research ( IF 3.7 ) Pub Date : 2020-06-18 , DOI: 10.1007/s11064-020-03073-4
Chen Cheng 1 , Nan Zheng 2 , Deyang Sun 3 , Weishuo Fang 3 , Lingling Zheng 4 , Weihong Song 4 , Jian Huang 1
Affiliation  

The abnormally accumulated amyloid-β (Aβ) and oxidative stress contribute to the initiation and progression of Alzheimer’s disease (AD). β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting enzyme for the production of Aβ. Furthermore, Aβ was reported to increase oxidative stress; then the overproduced oxidative stress continues to increase the expression and activity of BACE1. Consequently, inhibition of both BACE1 and oxidative stress is a better strategy for AD therapy compared with those one-target treatment methods. In the present study, our novel small molecule YS-5-23 was proved to possess both of the activities. Specifically, we found that YS-5-23 reduces BACE1’s expression in both SH-SY5Y and Swedish mutated amyloid precursor protein (APP) overexpressed HEK293 cells, and it can also suppress BACE1’s expression induced by H2O2. Moreover, YS-5-23 decreases H2O2-induced cytotoxicity including alleviating H2O2-induced apoptosis and loss of mitochondria membrane potential (MMP) because it attenuates the reactive oxygen species (ROS) level elevated by H2O2. Meanwhile, PI3K/Akt signaling pathway is involved in the anti-H2O2 and BACE1 inhibition effect of YS-5-23. Our findings indicate that YS-5-23 may develop as a drug candidate in the prevention and treatment of AD.



中文翻译:

新型化合物YS-5-23通过减少β-位淀粉样前体蛋白裂解酶1的表达和H2O2诱导的SH-SY5Y细胞的细胞毒性而表现出神经保护作用。

异常积累的淀粉样蛋白β(Aβ)和氧化应激有助于阿尔茨海默氏病(AD)的发生和发展。β位淀粉样蛋白前体蛋白裂解酶1(BACE1)是产生Aβ的限速酶。此外,据报道,Aβ会增加氧化应激。然后过度产生的氧化应激继续增加BACE1的表达和活性。因此,与那些单靶标治疗方法相比,抑制BACE1和氧化应激是AD治疗的更好策略。在本研究中,我们的新型小分子YS-5-23被证明具有两种活性。具体来说,我们发现YS-5-23降低了SH-SY5Y和瑞典突变型淀粉样前体蛋白(APP)过表达的HEK293细胞中BACE1的表达,2 O 2。此外,YS-5-23降低了H 2 O 2诱导的细胞毒性,包括减轻H 2 O 2诱导的细胞凋亡和线粒体膜电位(MMP)的损失,因为它减弱了H 2 O 2升高的活性氧(ROS)水平。。同时,PI3K / Akt信号通路参与了YS-5-23的抗H 2 O 2和BACE1抑制作用。我们的发现表明,YS-5-23可能会发展成为预防和治疗AD的候选药物。

更新日期:2020-08-12
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