Efficacy of Oleuropein Aglycone in the Treatment of Transthyretin-Amyloidosis

Diet in human health is no longer simple nutrition, but in light of recent epidemiological studies, it is may have deep effects on modulating apoptosis, detoxification, appropriate gene response and protection against disease. Recently, nutrigenomics research suggested that it is not just deficiency of a particular element but also the presence in diet in adequate amount of various other compounds from fruits and vegetables that play a role in decreasing risk of a range of disease including cancer cardiovascular and neurodegenerative disease. Our laboratory focused attention on the main phenolic compound, Oleuropein aglycone (OleA), of extra-virgin olive oil. The pharmacological properties of olive oil, especially the olive fruit and its leaves have been recognized as important components of medicine and a healthy diet for their phenolic content [1]. OleA has several pharmacological properties such as antioxidant [1], anti-inflammatory [2] anti-atherogenic [3], anti-cancer [4], antimicrobial [5] and antiviral [6], and for these reasons, it is commercially available as food supplement. In addition, it has been shown to be cardioprotective against acute adriamycin cardiotoxicity [7] and has been shown to exhibit antiischemic and hypolipidemic activities [8]. Another important aspect to be considered is that the OleA interaction with cell Abstract Transthyretin (TTR) is an amyloidogenic protein implicated in diseases such as senile systemic amyloidosis (SSA) and familial amyloid polyneuropathy (FAP), both characterized by extracellular deposition of insoluble amyloid fibrils in heart, peripheral nerves and other organs. In particular, fibrils in FAP patients are composed of single-site mutant TTR and among the numerous pathogenic variants Leu55 → Pro55 (L55P) is highly amyloidogenic and forms amyloid fibrils in vitro. TTR fibrils have been considered directly responsible of tissue impairment in FAP and SSA, but the unstable fibril precursors are increasingly considered the main responsible of cell sufferance and tissue impairment in amyloid diseases. The recent introduction in the clinical practice of synthetic TTR-stabilizing molecules that reduce protein aggregation provides the rationale to search natural effective molecules able to interfere with TTR amyloid aggregation by hindering the appearance of toxic species or by favouring the growth of harmless aggregates. We focused our study on the ability of Oleuropein aglycone (OleA), the main phenolic component of the extra virgin olive oil, to inhibit the toxic effects of wtand L55PTTR amyloid. Our data offer the possibility to validate and optimize the use of OleA as itself or as a starting point to rationally design promising drugs that could enter in a clinical experimental phase.