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

Siva Sundara Kumar Durairajan*, Venkat Reddy Chirasani, Sravan Gopalakrishnan Shetty, Ashok Iyaswamy, Sandeep Malampati, Juxian Song, Liangfeng Liu, Jiandong Huang, Sanjib Senapati, Min Li*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

17 Citations (Scopus)

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

Original languageEnglish
Pages (from-to)1229-1237
Number of pages9
JournalCurrent Alzheimer Research
Volume14
Issue number11
DOIs
Publication statusPublished - Nov 2017

Scopus Subject Areas

  • Neurology
  • Clinical Neurology

User-Defined Keywords

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

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