Salvianolic Acid B Inhibits Aβ Generation by Modulating BACE1 Activity in SH-SY5Y-APPsw Cells

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease in humans. The accumulation of amyloid-β (Aβ) plays a critical role in the pathogenesis of AD. Previous studies indicated that Salvianolic acid B (SalB) could ameliorate Aβ-induced memory impairment. However, whether SalB could influence the generation of Aβ is unclear. Here, we show that SalB (25, 50, or 100 µM) reduces the generation of Aβ40 and Aβ42 in culture media by decreasing the protein expressions of BACE1 and sAPPβ in SH-SY5Y-APPsw cells. Meanwhile, SalB increases the levels of ADAM10 and sAPPα in the cells. However, SalB has no impact on the protein expressions of APP and PS1. Moreover, SalB attenuates oxidative stress and inhibits the activity of GSK3β, which might be related to the suppression of BACE1 expression and amyloidogenesis. Our study suggests that SalB is a promising therapeutic agent for AD by targeting Aβ generation.

Natural Compounds with Anti-BACE1 Activity as Promising Therapeutic Drugs for Treating Alzheimerʼs Disease

“…Tang et al and Durairajan et al independently reported that Sal B modulated BACE1 activity in SH-SY5Y-APPsw cells and it decreased Aβ generation in H4-SwedAPP, N2a-SwedAPP, and HEK-BACE1 cells. Many, possibly important, variations can be noticed in these studies: i) Tang et al suggested that BACE1 expression was reduced at 50 µM [53], but Durairajan et al [54] showed that Sal B 8 [55] reported that Sal B shows negligible binding to the catalytic sites using molecular docking methods. Tang et al suggest that Sal B suppresses BACE1 expression.…”

Molecular Pharmacology of Rosmarinic and Salvianolic Acids: Potential Seeds for Alzheimer’s and Vascular Dementia Drugs

“…A summary of in vitro effects that attributes to the potential therapeutic effects of salvianolic acid derivatives are shown in Table 1 [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. By assessing the β-secretase (β-site amyloid precursor protein (APP) cleaving enzyme or BACE1) and γ-secretase inhibitory activity, a selective effect against BACE1 was demonstrated for SA-B [ 32 ].…”

“…Moreover, the direct interaction of the compound with the catalytic center of the enzyme has been confirmed by docking experiments [ 32 ]. In SH-SY5Y-APPsw cells, the Aβ40 and Aβ42 levels in culture media has been shown to be suppressed by SA-B [ 33 ]. While the protein expression of APP was not affected by SA-B, it has been shown to increase the protein level expressions of “a disintegrin and metalloproteinase domain-containing protein 10” (ADAM10) and secreted APP-α (sAPPα) concomitantly with the decreased protein expressions of BACE1 and sAPPβ [ 33 ].…”

“…In SH-SY5Y-APPsw cells, the Aβ40 and Aβ42 levels in culture media has been shown to be suppressed by SA-B [ 33 ]. While the protein expression of APP was not affected by SA-B, it has been shown to increase the protein level expressions of “a disintegrin and metalloproteinase domain-containing protein 10” (ADAM10) and secreted APP-α (sAPPα) concomitantly with the decreased protein expressions of BACE1 and sAPPβ [ 33 ]. Such observation is in perfect agreement with the postulated mechanism of action via inhibition of Aβ formation ( Figure 3 ).…”

“…The effect of SA-B in suppressing the cardiotoxicity of doxorubicin is also mediated through antioxidant mechanism [ 49 ]. SA-B could also inhibit GSK3β by increasing the ratio of pSer9-GSK3β to total GSK3β [ 33 ].…”