The formation of amyloid beta-protein (1-42) (A beta 42) oligomers and A beta 42 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 A beta 42 monomers by inhibiting their aggregation and by working in a manner similar to synergy with A beta 42 monomers. Moreover, Mat could also exert a cytoprotective effect by actively promoting the disaggregation of immature A beta 42 oligomers in a concentration-dependent manner. Although Mat at intermediate concentrations (1-50 mu M) exhibited both cytotrophic and cytoprotective effects on SH-SY5Y cells, Mat at higher concentrations (100 mu M) only exhibited a cytoprotective effect. Molecular docking studies reveal that these differences are a result of the different interactions between Mat and A beta 42 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 A beta 42 monomers. A deficiency in this chaperone would result in the gradual aggregation of A beta 42 monomers, and eventually, formation of toxic A beta 42 oligomers. In addition, reduction or clearance of A beta 42 aggregates or deposits and inhibition or elimination of the toxicity of oligomeric A beta 42, were not always directly correlated. Finally, the site(s) responsible for cytotoxicity in A beta 42 oligomers may be located in the integrated region of the N-terminal fragments of A beta 42 chains. This study provides valuable insights into the mechanisms involved in the development of natural drugs for the treatment of Alzheimer's disease.