The Resveratrol Trimer Miyabenol C Inhibits β-Secretase Activity and β-Amyloid Generation

Abstract

Accumulation and deposition of amyloid- peptide (A) in the brain is a primary cause of the pathogenesis of Alzheimer's disease (AD). A is generated from amyloid- precursor protein (APP) through sequential cleavages first by -secretase and then by -secretase. Inhibiting -secretase activity is believed to be one of the most promising strategies for AD treatment. In the present study, we found that a resveratrol trimer, miyabenol C, isolated from stems and leaves of the small-leaf grape (Vitisthunbergii var. taiwaniana), can markedly reduce A and sAPP levels in both cell cultures and the brain of AD model mice. Mechanistic studies revealed that miyabenol C affects neither protein levels of APP, the two major -secretases ADAM10 and TACE, and the -secretase component Presenilin 1, nor -secretase-mediated Notch processing and TACE activity. In contrast, although miyabenol C has no effect on altering protein levels of the -secretase BACE1, it can inhibit both in vitro and in vivo -secretase activity. Together, our results indicate that miyabenol C is a prominent -secretase inhibitor and lead compound for AD drug development.