E-Mail karger@karger.com Original Paper Neurodegener Dis DOI: 10.1159/000355557 Gamma-Secretase Inhibitor Activity of a Pterocarpus erinaceus Extract Salim Hage   a Claudia Marinangeli   b Serena Stanga   b Jean-Noël Octave   b Joëlle Quetin-Leclercq   a Pascal Kienlen-Campard   b a  Louvain Drug Research Institute and b  Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium that this extract inhibited γ-secretase activity in cell-free and in vitro assays, strongly suggesting that P. erinaceus extract is a natural γ-secretase inhibitor. Importantly, this extract did not inhibit γ-secretase-dependent Notch intracellular do- main release. Conclusion: P. erinaceus extract appears as a new potent γ-secretase inhibitor selective towards APP pro- cessing. © 2013 S. Karger AG, Basel Introduction The β-amyloid peptide (Aβ) accumulation in the brain is the key event in Alzheimer’s disease (AD) amyloid cas- cade [1]. This can be due to Aβ peptide excessive produc- tion, its reduced clearance and/or impaired transport through the blood brain barrier. Aβ can trigger neuronal damage in different ways, e.g. by aggregating into senile plaques causing oxidative stress in the surrounding neu- rons and synapse disorders, by forming toxic soluble oligomers or by intraneuronal accumulation leading to neuronal apoptosis [2–4]. The metabolic pathways involved in Aβ production have been extensively studied in the last two decades [5, 6], leading to the identification of the amyloidogenic secretases, namely β- and γ-secretases. β-Secretase cleaves Key Words Alzheimer’s disease · Amyloid precursor protein · β-Amyloid peptide · γ-Secretase inhibitor · Pharmacognosy · Pterocarpus erinaceus Abstract Background: Accumulation of β-amyloid peptides (Aβ) and its progressive deposition into amyloid plaques are key events in the aetiology of Alzheimer’s disease (AD). To date, AD treatment is symptomatic and consists of drugs treating the cognitive decline. Objective: Identifying molecules spe- cifically targeting Aβ production or aggregation represents a huge challenge in the development of specific AD treat- ments. Several molecules reported as γ-secretase inhibitors or modulators have been evaluated, but so far none of them have proven to be selective or fully efficient. We have previ- ously investigated the potential interest of plant extracts and we reported that Pterocarpus erinaceus stem-bark ex- tract was active on Aβ release. Our aim here was to charac- terize the mechanisms by which this extract reduces Aβ lev- els. Methods: We tested P. erinaceus extract at non-toxic con- centrations on cells expressing the human amyloid precursor protein (APP695) or its amyloidogenic β-cleaved C-terminal fragment (C99), as well as on neuronal cell lines. P. erinaceus extract was found to inhibit Aβ release. We further showed Received: December 3, 2012 Accepted after revision: September 10, 2013 Published online: October 30, 2013 Diseases Pascal Kienlen-Campard Université catholique de Louvain, Institute of Neuroscience Avenue Mounier 53 (box B1.53.02) BE–1200 Brussels (Belgium) E-Mail pascal.kienlen-campard  @  uclouvain.be © 2013 S. Karger AG, Basel 1660–2854/13/0000–0000$38.00/0 www.karger.com/ndd Downloaded by: Universitätsbibliothek Heidelberg 147.142.106.81 - 11/4/2013 8:59:55 AM