Dengzhan Shengmai capsules and their active component scutellarin prevent cognitive decline in APP/PS1 mice by accelerating Aβ aggregation and reducing oligomers formation

Abstract

There is currently no effective treatment to prevent the progress of Alzheimer’s disease (AD). The traditional Chinese herbs Dengzhan Shengmai (DZSM) capsules and their active component scutellarin possess multiple effects and are clinically used for the treatment of cerebrovascular diseases. Scutellarin has been reported to affect Aβ aggregation. However, the effects of DZSM capsules on AD remain unknown. Through in vivo experiments, our study proved that the alleviating effects of DZSM capsules on cognitive deficits of AD mice were due to the role of scutellarin, which up-regulated low toxic amyloid plaques and down-regulated highly toxic soluble Aβ42 and Aβ40 levels in cortex. In vitro, we confirmed scutellarin’s role in accelerating transforming Aβ42 monomers into high-molecular-mass aggregates by biochemical assays, which supported the results observed in drug-treated APP/PS1 mice. In detail, the 1:10 ratio of scutellarin/Aβ42 mixtures promoted production of large β-sheet-rich fibrils whereas the 1:1 ratio promoted production of protofibrils. In addition, the binding between scutellarin and Aβ monomers was quantified by microscale thermophoresis test and the apparent dissociation constant (Kd) was 1284.4 ± 238.8 μM. What’s more, binding regions between scutellarin and Aβ fibrils were predicted by computational docking models and scutellarin might bind parallel to the long axis of Aβ42 fibrils targeting hydrophobic grooves at residues 35–36 or 39. In conclusion, DZSM capsules protected against cognitive defects of AD through scutellarin-mediated acceleration of Aβ aggregation into fibrils or protofibrils and reduction of soluble Aβ oligomers, thus suggesting potential clinical applications of DZSM capsules and scutellarin in the treatment of AD.