title: The resveratrol trimer miyabenol C inhibits β-secretase activity and β-amyloid generation.
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.
authors: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China; Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, 361102, China.
authors: Jin
authors: J
authors: Hu
authors: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
authors: Ting
authors: T
authors: Lin
authors: Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, 361102, China.
authors: Yuehong
authors: Y
authors: Gao
authors: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
authors: Junyue
authors: J
authors: Xu
authors: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
authors: Chao
authors: C
authors: Jiang
authors: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
authors: Guanghui
authors: G
authors: Wang
authors: Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, 361102, China.
authors: Guojun
authors: G
authors: Bu
authors: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China; Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, 361102, China.
authors: Huaxi
authors: H
authors: Xu
authors: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
authors: Haifeng
authors: H
authors: Chen
authors: Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, 361102, China.
authors: Yun-wu
authors: YW
authors: Zhang
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D059748:Proteolysis; D012995:Solubility / Q000187:drug effects; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001572:Benzofurans; D010936:Plant Extracts; D013267:Stilbenes; C585842:miyabenol C; D053829:Amyloid Precursor Protein Secretases
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