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Curr Alzheimer Res. 2017;14(11):1229-1237. doi: 10.2174/1567205014666170417103003.

Decrease in the Generation of Amyloid-β Due to Salvianolic Acid B by Modulating BACE1 Activity.

Author information

1
Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, No.7, Baptist University Road, Kowloon Tong, Hong Kong. China.
2
Department of Biotechnology, Indian Institute of Technology Madras, Chennai. India.
3
Neuroscience Research Laboratory, Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong. China.
4
Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam Road, Hong Kong. China.

Abstract

OBJECTIVE:

Generation and accumulation of the amyloid-β (Aβ) peptide after proteolytic processing of the full length amyloid precursor protein (FL-APP) by β-secretase (β-site APP cleaving enzyme or BACE1) and γ-secretase are the main causal factors of Alzheimer's disease (AD). Thus, inhibition of BACE1, a rate-limiting enzyme in the production of Aβ, is an attractive therapeutic approach for the treatment of AD. Recent studies suggest that salvianolic acid B (Sal B) is isolated from the radix of Salvia miltiorrhiza Bunge, a Chinese herbal medicine commonly used for the treatment of cardiovascular, cerebrovascular and liver diseases in China.

METHOD:

In this study, we discovered that Sal B acted as a BACE1 modulator and reduced the level of secreted Aβ in two different Swedish APP (SwedAPP) mutant cell lines. Using N2a-mouse and H4- human neuroglioma cell lines expressing SwedAPP, it was demonstrated that Sal B significantly and dose-dependently decreased the generation of extracellular Aβ, soluble APPβ (by-product of APP cleaved by BACE1), and intracellular C-terminal fragment β from APP without influencing α-secretase and γ-secretase activity and the levels of FL-APP. In addition, using protein-docking, we determined the potential conformation of Sal B on BACE1 docking and revealed the interactions of Sal B with the BACE1 catalytic center.

RESULTS:

The docking provides a feasible explanation for the experimental results, especially in terms of the molecular basis of Sal B's action. Our results indicate that Sal B is a BACE1 inhibitor and, as such, is a promising candidate for the treatment of AD.

KEYWORDS:

Aβ generation; BACE-1; Docking; Salvianolic acid B; Soluble amyloid precursor protein-β; Traditional Chinese medicine

[Indexed for MEDLINE]

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