A Novel Compound YS-5-23 Exhibits Neuroprotective Effect by Reducing β-Site Amyloid Precursor Protein Cleaving Enzyme...

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.