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A Pentacyclic Triterpene from Ligustrum lucidum Targets γ-Secretase.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-08-10 , DOI: 10.1021/acschemneuro.0c00389
Wenjie Luo 1 , Fanny C F Ip 2, 3, 4 , Guangmiao Fu 2 , Kit Cheung 2 , Yuan Tian 1 , Yueqing Hu 2 , Anjana Sinha 1 , Elaine Y L Cheng 2 , Xianzhong Wu 5 , Victor Bustos 1 , Paul Greengard 1 , Yue-Ming Li 5 , Subhash C Sinha 1 , Nancy Y Ip 2, 3, 4
Affiliation  

Amyloid-beta peptides generated by β-secretase- and γ-secretase-mediated successive cleavage of amyloid precursor protein are believed to play a causative role in Alzheimer’s disease. Thus, reducing amyloid-beta generation by modulating γ-secretase remains a promising approach for Alzheimer’s disease therapeutic development. Here, we screened fruit extracts of Ligustrum lucidum Ait. (Oleaceae) and identified active fractions that increase the C-terminal fragment of amyloid precursor protein and reduce amyloid-beta production in a neuronal cell line. These fractions contain a mixture of two isomeric pentacyclic triterpene natural products, 3-O-cis- or 3-O-trans-p-coumaroyl maslinic acid (OCMA), in different ratios. We further demonstrated that trans-OCMA specifically inhibits γ-secretase and decreases amyloid-beta levels without influencing cleavage of Notch. By using photoactivatable probes targeting the subsites residing in the γ-secretase active site, we demonstrated that trans-OCMA selectively affects the S1 subsite of the active site in this protease. Treatment of Alzheimer’s disease transgenic model mice with trans-OCMA or an analogous carbamate derivative of a related pentacyclic triterpene natural product, oleanolic acid, rescued the impairment of synaptic plasticity. This work indicates that the naturally occurring compound trans-OCMA and its analogues could become a promising class of small molecules for Alzheimer’s disease treatment.

中文翻译:

来自女贞子的五环三萜靶向 γ-分泌酶。

β-分泌酶和 γ-分泌酶介导的淀粉样前体蛋白的连续裂解产生的淀粉样 β 肽被认为在阿尔茨海默病中起致病作用。因此,通过调节 γ-分泌酶减少淀粉样蛋白 β 的产生仍然是阿尔茨海默病治疗开发的一种有前途的方法。在这里,我们筛选了女贞子Ait 的果实提取物。(木犀科)并确定了增加淀粉样前体蛋白 C 末端片段并减少神经元细胞系中淀粉样蛋白 β 产生的活性组分。这些馏分包含两种异构五环三萜天然产物的混合物,3- O -顺式- 或 3- O -反式- p-香豆酰山楂酸 (OCMA),不同比例。我们进一步证明反式OCMA 特异性抑制 γ-分泌酶并降低淀粉样蛋白-β 水平而不影响 Notch 的切割。通过使用靶向位于 γ-分泌酶活性位点的亚位点的可光活化探针,我们证明反式OCMA 选择性地影响该蛋白酶中活性位点的 S1 亚位点。用反式OCMA 或相关五环三萜天然产物齐墩果酸的类似氨基甲酸酯衍生物治疗阿尔茨海默病转基因模型小鼠,挽救了突触可塑性的损伤。这项工作表明,天然存在的化合物反式-OCMA 及其类似物可能成为治疗阿尔茨海默病的一类有前途的小分子。
更新日期:2020-09-16
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