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 L55P- TTR 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.
Highlights
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
The present review will describe the biological effects of Oleuropein aglycone (OleA) with particular attention on the molecular mechanism underlying the protective action against TTR amyloidosis toxicity
These studies showed that all these compounds stabilize the TTR and inhibit amyloid aggregation by three different means: epigallocatechin 3-gallate (EGCG) strongly suppresses the dissociation of the TTR tetramer maintaining it as a soluble protein; curcumin induces the oligomerization of TTR in a characteristic homogeneous population of non-toxic "offpathway" small aggregates and nordihydroguaiaretic acid (NDGA) moderately reduces the amount of aggregated TTR [18]
Summary
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. OleA was shown to modify Amyloid Precursor Protein- (APP) processing, increasing the formation of the non-amyloidogenic and neuroprotective sAPPα fragment and to decrease Aβ oligomers in HEK695 cell supernatants by increasing matrix metalloproteinase-9 (MMP9) secretion [15]. These results are very promising and pave the way to a more extensive investigation on OleA ability to inhibit toxic amyloid aggregation of many other amyloid-associated peptides/proteins. The present review will describe the biological effects of OleA with particular attention on the molecular mechanism underlying the protective action against TTR amyloidosis toxicity
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