The formation of amyloid β-protein (1-42) (Aβ42) oligomers and Aβ42 oligomer cytotoxicity are two defining characteristics of the etiology of Alzheimer’s disease (AD). In this study, we found that matrine (Mat) could maintain or even enhance the cytotrophic effect of Aβ42 monomers by inhibiting their aggregation and by working in a manner similar to synergy with Aβ42 monomers. Moreover, Mat could also exert a cytoprotective effect by actively promoting the disaggregation of immature Aβ42 oligomers in a concentration-dependent manner. Although Mat at intermediate concentrations (1-50 μM) exhibited both cytotrophic and cytoprotective effects on SH-SY5Y cells, Mat at higher concentrations (100 μM) only exhibited a cytoprotective effect. Molecular docking studies reveal that these differences are a result of the different interactions between Mat and Aβ42 oligomers that occur at different molecular ratios. Our results support the hypothesis that there may be a Mat-like metabolite in the human brain that acts as a molecular chaperone for Aβ42 monomers. A deficiency in this chaperone would result in the gradual aggregation of Aβ42 monomers, and eventually, formation of toxic Aβ42 oligomers. In addition, reduction or clearance of Aβ42 aggregates or deposits and inhibition or elimination of the toxicity of oligomeric Aβ42, were not always directly correlated. Finally, the site(s) responsible for cytotoxicity in Aβ42 oligomers may be located in the integrated region of the N-terminal fragments of Aβ42 chains. This study provides valuable insights into the mechanisms involved in the development of natural drugs for the treatment of Alzheimer’s disease.Copyright © 2020. Published by Elsevier Ltd.