The resveratrol trimer miyabenol C inhibits β-secretase activity and β-amyloid generation.

Jin Hu,Guojun Bu,Guanghui Wang,Huaxi Xu,Junyue Xu,Chao Jiang,Yun-Wu Zhang,Haifeng Chen,Yuehong Gao,Ting Lin,Masuo Ohno

doi:10.1371/journal.pone.0115973

Abstract

Accumulation and deposition of amyloid-β peptide (Aβ) in the brain is a primary cause of the pathogenesis of Alzheimer’s disease (AD). Aβ is generated from amyloid-β precursor protein (APP) through sequential cleavages first by β-secretase and then by γ-secretase. Inhibiting β-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 Aβ and sAPPβ 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 α-secretases ADAM10 and TACE, and the γ-secretase component Presenilin 1, nor γ-secretase-mediated Notch processing and TACE activity. In contrast, although miyabenol C has no effect on altering protein levels of the β-secretase BACE1, it can inhibit both in vitro and in vivo β-secretase activity. Together, our results indicate that miyabenol C is a prominent β-secretase inhibitor and lead compound for AD drug development.

Highlights

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by impaired memory and cognition
N2a cells stably expressing human APP695 (N2a695) cells were treated with increasing doses of miyabenol C (0, 0.1, 1, 5, 10, 20, 40, 80, 100μM) for 10h and cell viability was evaluated by Cell Counting Kit-8 (CCK-8) assay
The results showed that miyabenol C had no cytotoxicity at lower doses (5–20μM) but showed a dose-dependent cytotoxicity at higher doses (40–100μM) (Fig. 1B)

Summary

Introduction

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by impaired memory and cognition. One of the major pathological hallmarks of AD in the brain is senile plaques, which are composed of heterozygous amyloid-β (Aβ) peptides. Ample evidence indicates that accumulation of Aβ peptides in vulnerable brain regions plays a central role in AD pathogenesis: Aβ is neurotoxic and can trigger a cascade of neurodegenerative steps including the formation of senile plaques and neurofibrillary tangles, synaptic dysfunction, and eventual neuronal loss [1, 2]. Aβ is a proteolytic product of the amyloid-β precursor protein (APP) and is generated through sequential cleavages by enzymes called β- and γ-secretases. During this amyloidogenic processing, β-secretase first cleaves the type I transmembrane APP protein.

Methods

Results

Conclusion