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Natural polyphenols as modulators of TTR amyloidogenesis: in vitro and in vivo evidences towards therapy

Several natural polyphenols have been reported to act on different amyloidogenic proteins inhibiting amyloid formation therefore we decided to test their effect on transthyretin (TTR) amyloid formation. We found that epigallocatechin-3-gallate (EGCG), curcumin and nordihydroguaiaretic acid (NDGA) bind to TTR and modulate its amyloidogenicity, in vitro, although through different mechanisms of action. Based on these in vitro studies, we decided to test EGCG in vivo using mice models for familial amyloidotic polyneuropathy (FAP). Therefore, we performed a subchronic administration of EGCG to mice, for 6 weeks. Next, we assessed the effects of EGCG treatment by immunohistochemistry (IHC) and western blot analysis of mice tissues. The results obtained demonstrate that EGCG inhibits TTR aggregates deposition in about 50% along the gastrointestinal (GI) tract and peripheral nervous system (PNS) and lowered the levels of several FAP associated biomarkers. Furthermore, treatment of old FAP mice with EGCG resulted not only in the decrease of nonfibrillar TTR deposition but also in the disaggregation of congophilic amyloid deposits. The dual effect as inhibitor of aggregation and as disruptor of amyloid together with its low toxicity indicates that EGCG presents a therapeutic application in FAP.