The inhibitory effects of berbamine hydrochloride (BBMH) on Aβ aggregation were comprehensively evaluated using several widely-used biophysical assays. Furthermore, the inhibitory mechanisms of BBMH were elucidated through SPR analysis and chemical kinetics analysis. These findings suggest that bisbenzylisoquinoline alkaloids hold great promise in the battle against Alzheimer's disease.

Abstract

Alzheimer's disease (AD) continues to be a major global health challenge, and the recent approval of Aduhelm and Leqembi has opened new avenues for its treatment. Small-molecule inhibitors targeting Aβ aggregation hold promise as an alternative to monoclonal antibodies. In this study, we evaluated the ability of berbamine hydrochloride (BBMH), a member of the bisbenzylisoquinoline alkaloids, to reduce Aβ aggregation and cytotoxicity. Thioflavin T kinetics, circular dichroism spectroscopy, and atomic force microscopy results indicated that BBMH effectively inhibited Aβ aggregation. Surface plasmon resonance and molecular docking results further revealed that BBMH could bind to Aβ fibrils, thereby hindering the aggregation process. This physical picture has been confirmed in a quantitative way by chemical kinetics analysis, which showed BBMH tends to bind with the fibril ends and thus prevents the transition from protofibrils to mature fibrils as well as the elongation process. Additionally, our MTT results showed that BBMH was able to reduce the cytotoxicity of Aβ40 on N2a cells. Our results demonstrate, for the first time, the potential of BBMH to inhibit Aβ aggregation and cytotoxicity, offering a promising direction for further research and drug development efforts in the fight against Alzheimer's disease.