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A Pentacyclic Triterpene from Targets γ-Secretase.

TitleA Pentacyclic Triterpene from Targets γ-Secretase.
Publication TypeJournal Article
Year of Publication2020
AuthorsLuo W, Ip FCF, Fu G, Cheung K, Tian Y, Hu Y, Sinha A, Cheng EYL, Wu X, Bustos V, Greengard P, Li Y-M, Sinha SC, Ip NY
JournalACS Chem Neurosci
Volume11
Issue18
Pagination2827-2835
Date Published2020 Sep 16
ISSN1948-7193
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 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--- or 3----coumaroyl maslinic acid (OCMA), in different ratios. We further demonstrated that -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 -OCMA selectively affects the S1 subsite of the active site in this protease. Treatment of Alzheimer's disease transgenic model mice with -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 -OCMA and its analogues could become a promising class of small molecules for Alzheimer's disease treatment.

DOI10.1021/acschemneuro.0c00389
Alternate JournalACS Chem Neurosci
PubMed ID32786303