Screening for amyloid-β aggregation inhibitor and neuronal toxicity of eight Tunisian medicinal plants

Abstract

The aggregation and deposition of misfolded β-amyloid peptide (Aβ42) is a consistent pathological hallmark of Alzheimer Disease (AD). Mounting pieces of evidence indicate that the auto-assembly of Aß42 into toxic oligomers and fibrillar aggregates is a multi-steps process that causes an increase of ROS (Reactive oxygen species) level, disruption of calcium homeostasis and altered membrane integrity leading to neuronal death. Oxidation is thought to promote Aß42 aggregation, so the use of natural dietary antioxidants that can interfere or inhibit Aß aggregation and its cytotoxicity is a promising approach. In this study, we investigate a panel of extracts from eight Tunisian medicinal plants for their ability to counteract amyloid aggregation. A screening assay was developed to identify and to rank extracts that hinder Aβ aggregation. Thus, we report that secondary metabolites extracted from Lawsonia inermis L., Punica granatum L. and Pistacia lentiscus L. hinder Aβ42 aggregation during the early secondary structure transitions to amyloid by inhibiting the conformational changes to a β sheet-rich structure, thus inhibiting its polymerization and fibrillogenisis. Cellular study allowed us to select the extract of L. inermis as the most bioactive extract; we showed that the extract of L. inermis reduces the toxicity, ROS and calcium levels induced by Aß42 aggregates. FRET analysis confirmed the ability of the extract of L. inermis to inhibit the interaction between Aβ42 aggregates and plasma membrane, thus reducing their cytotoxicity. These results suggested that methanolic extract from L. inermis could act as neuroprotective and therapeutic factors against toxic Aβ aggregates.