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

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 (2020). https://doi.org/10.1007/s11064-020-03073-4

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Keywords

  • Alzheimer’s disease
  • BACE1
  • Oxidative stress
  • PI3K/Akt