TY - JOUR
T1 - The resveratrol trimer miyabenol C inhibits β-secretase activity and β-amyloid generation
AU - Hu, Jin
AU - Lin, Ting
AU - Gao, Yuehong
AU - Xu, Junyue
AU - Jiang, Chao
AU - Wang, Guanghui
AU - Bu, Guojun
AU - Xu, Huaxi
AU - Chen, Haifeng
AU - Zhang, Yun Wu
N1 - Funding Information:
We thank Dr. Robert Vassar at Northwestern University for providing the BACE1 antibody 3D5 and Dr. Chi-Luan Wen at Taiwan Seed Improvement and Propagation Station for providing Plant material. This work was supported by National Natural Science Foundation of China (Nos. 81202419, 81225008, 81161120496, 91332112, and 91332114), Xiamen Science and Technology Key program grant (No. 3502Z20100006), and Fundamental Research Funds for the Central Universities of China.
Publisher Copyright:
© 2015 Hu et al.
PY - 2015/1/28
Y1 - 2015/1/28
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0115973
DO - 10.1371/journal.pone.0115973
M3 - Article
C2 - 25629409
AN - SCOPUS:84961291056
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 1
M1 - e0115973
ER -