A Pentacyclic Triterpene from Targets γ-Secretase

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.