TY - JOUR
T1 - Decrease in the Generation of Amyloid-β Due to Salvianolic Acid B by Modulating BACE1 Activity
AU - Durairajan, Siva Sundara Kumar
AU - Chirasani, Venkat Reddy
AU - Shetty, Sravan Gopalakrishnan
AU - Iyaswamy, Ashok
AU - Malampati, Sandeep
AU - Song, Juxian
AU - Liu, Liangfeng
AU - Huang, Jiandong
AU - Senapati, Sanjib
AU - Li, Min
N1 - Publisher copyright:
© 2017 Bentham Science Publishers.
PY - 2017/11
Y1 - 2017/11
N2 - 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
AB - 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
KW - Aβ generation
KW - BACE-1
KW - Docking
KW - Salvianolic acid B
KW - Soluble amyloid precursor protein-β
KW - Traditional Chinese medicine
UR - http://www.scopus.com/inward/record.url?scp=85040069393&partnerID=8YFLogxK
U2 - 10.2174/1567205014666170417103003
DO - 10.2174/1567205014666170417103003
M3 - Journal article
C2 - 28413985
AN - SCOPUS:85040069393
SN - 1567-2050
VL - 14
SP - 1229
EP - 1237
JO - Current Alzheimer Research
JF - Current Alzheimer Research
IS - 11
ER -