Hage, Salim
[UCL]
(eng)
Alzheimer’s disease (AD) is the most frequent cause of dementia and its prevalence is considerably increasing with the elderly population. Research for new drugs, able to stop the progression of this incurable disease, constitutes an urgent major challenge for public health.
AD is due to a neuronal loss, characterized by the presence of two neuropathological lesions, mainly in hippocampus and cerebral cortex: neurofibrillary tangles containing intracellular protein tau in a hyperphosphorylated and microtubule-dissociated form, and extracellular senile plaques containing polymerized β-amyloid peptide (Aβ). This peptide is generated by the sequential cleavage of the transmembrane protein APP (Aβ precursor protein) by a β-secretase followed by a γ-secretase complex. Aβ does not only aggregate into plaques, causing synapse disorders and the death of neighbouring neurons, but also causes neuronal apoptosis by its intracellular accumulation as well as through its diffusible soluble oligomers. The important role of this peptide in the pathology led us to choose its production as target.
Vegetal kingdom has been and still is a very wide source of original biologically active compounds, which continue to enrich our drug armamentarium; several publications relate the activity of vegetal compounds against AD-related mechanisms. We first screened, on Aβ production in a CHO-APP model, several extracts made from nine plants used in traditional medicine in Benin and in Madagascar against memory disorders. The most active plant was the proanthocyanidin-rich tree Pterocarpus erinaceus Poiret. We decided to further study Pterocarpus erinaceus stem-bark aqueous extract and its kino aqueous extract, which was active even after tannin removal.
We tested both extracts on several cellular and membrane models to determine their mechanism of action. Both extracts decreased Aβ production in a concentration-dependant manner by inhibiting the γ-secretase-mediated cleavage of APP. This inhibition was found to be selective, since, on the contrary of standard γ-secretase inhibitors like DAPT, the extracts did not interfere with γ-secretase-mediated cleavage of Notch, nor does it decrease AICD liberation from APP.
The extracts were also submitted to bioguided fractionation, but activity was found in several fractions. We analysed active fractions by HPLC-MS and TLC-MS, and several phytochemical classes were therein detected, including catechic derivatives and saponosides. Epicatechin was found as the only monomer unit of the catechic tannins of the stem-bark and of the kino.
It is here the first report of an APP-selective γ-secretase modulating activity found in natural sources, and the first report of γ-secretase inhibiting activity found by an ethnophar¬maco¬logical approach. Pterocarpus erinaceus stem-bark and kino appear thus to be promising for the research of compounds to treat amyloidosis in Alzheimer’s disease.
Bibliographic reference |
Hage, Salim. Etude de l'action d'extraits tirés de plantes africaines traditionnellement utilisées en cas de démence sénile, sur le métabolisme du peptide bêta-amyloïde. Prom. : Quetin-Leclercq, Joëlle |
Permanent URL |
http://hdl.handle.net/2078.1/126515 |