A pentacyclic triterpene from Ligustrum lucidum targets γ-secretase Journal Article
| Authors: | Luo, W.; Ip, F. C. F.; Fu, G.; Cheung, K.; Tian, Y.; Hu, Y.; Sinha, A.; Cheng, E. Y. L.; Wu, X.; Bustos, V.; Greengard, P.; Li, Y. M.; Sinha, S. C.; Ip, N. Y. |
| Article Title: | A pentacyclic triterpene from Ligustrum lucidum targets γ-secretase |
| Abstract: | 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. |
| Keywords: | synaptic plasticity; amyloid precursor protein; secretase; oleanolic acid; beta-amyloid; alzheimer’s disease |
| Journal Title: | ACS Chemical Neuroscience |
| Volume: | 11 |
| Issue: | 18 |
| ISSN: | 1948-7193 |
| Publisher: | American Chemical Society |
| Date Published: | 2020-09-16 |
| Start Page: | 2827 |
| End Page: | 2835 |
| Language: | English |
| DOI: | 10.1021/acschemneuro.0c00389 |
| PUBMED: | 32786303 |
| PROVIDER: | scopus |
| PMCID: | PMC8325170 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 October 2020 -- Source: Scopus |
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