Synergetic effect of matrine on the catalytic scFv antibody HS72 in vitro and in mice with Alzheimer disease pathology

Single-chain variable fragment (scFv) HS72 is a catalytic antibody that specifically degrades amyloid beta-protein 1-42 (A beta 42) aggregates in vitro or reduces the level or burden of A beta 42 deposits/plaques in the brains of mice with Alzheimer disease pathology. Its efficacy has been shown in protecting neural cells in vitro and improving the morphology of the cell population in the brain of mice with AD pathology (AD mice). Matrine (Mat) is a natural product capable of binding to A beta 42 or its aggregates and blocking their neurotoxicity at concentrations of at least 10 mu M or greater. However, this study revealed a synergistic effect of Mat on the catalytic effect of HS72 at low concentrations (0.01-2.5 mu M). This is evidenced by the fact that Mat synergistically enhances HS72's ability to degrade A beta 42 aggregates and protect neural cells (SH-SY5Y and HT22 cells, and brain cells of AD mice). The molecular docking models and characterization of Mat's action both indicated that the mechanism of Mat's synergistic impact on HS72 catalysis is to increase the turnover number (or molecular activity) of HS72 by enhancing the catalytic power of the HS72's catalytic groups and encouraging the release of the degradation products (A beta fragments). The study's results suggest a natural synergy between Mat-like small molecules and the catalytic anti-oligomeric A beta 42 antibody HS72, enabling more effective reduction or removal of A beta 42 aggregates or plaques than the antibody alone. These findings provide novel insights into the effectiveness of anti-oligomeric A beta 42 antibodies in AD immunotherapy.