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.

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。