Abstract
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.
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Abbreviations
- AD:
-
Alzheimer's disease
- Aβ:
-
Amyloid-β
- APP:
-
Amyloid precursor protein
- BACE1:
-
β-Site amyloid precursor protein cleaving enzyme 1
- ROS:
-
Reactive oxygen species
- H2O2 :
-
Hydrogen peroxide
- Lu:
-
Luteolin
- CA:
-
P-hydroxy-cinnamic acid
- YS:
-
YS-5-23
- MMP:
-
Mitochondria membrane potential
- MDA:
-
Malondialdehyde
- SOD:
-
Superoxide dismutase
- PI3K:
-
Phosphoinositide 3-kinase
- GSK3β:
-
Glycogen synthase kinase-3β
- CREB:
-
CAMP response element-binding protein
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Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (31870786 and 31371331 to J. H., 81273406 to W.-S. F.), and the Drug Innovation Major Project (Grant Nos. 2018ZX09711001-001-001 and 2018ZX09711001-001-003).
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Cheng, C., Zheng, N., Sun, D. et al. 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. Neurochem Res 45, 2113–2127 (2020). https://doi.org/10.1007/s11064-020-03073-4
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DOI: https://doi.org/10.1007/s11064-020-03073-4