Epigallocatechin gallate (EGCG) reduces the intensity of pancreatic amyloid fibrils in human islet amyloid polypeptide (hIAPP) transgenic mice

Abstract

The formation of amyloid fibrils by human islet amyloid polypeptide protein (hIAPP) has been implicated in pancreas dysfunction and diabetes. However, efficient treatment options to reduce amyloid fibrils in vivo are still lacking. Therefore, we tested the effect of epigallocatechin gallate (EGCG) on fibril formation in vitro and in vivo. To determine the binding of hIAPP and EGCG, in vitro interaction studies were performed. To inhibit amyloid plaque formation in vivo, homozygous (tg/tg), hemizygous (wt/tg), and control mice (wt/wt) were treated with EGCG. EGCG bound to hIAPP in vitro and induced formation of amorphous aggregates instead of amyloid fibrils. Amyloid fibrils were detected in the pancreatic islets of tg/tg mice, which was associated with disrupted islet structure and diabetes. Although pancreatic amyloid fibrils could be detected in wt/tg mice, these animals were non-diabetic. EGCG application decreased amyloid fibril intensity in wt/tg mice, however it was ineffective in tg/tg animals. Our data indicate that EGCG inhibits amyloid fibril formation in vitro and reduces fibril intensity in non-diabetic wt/tg mice. These results demonstrate a possible in vivo effectiveness of EGCG on amyloid formation and suggest an early therapeutical application.

Phytochemical profiling, polyphenol composition, and antioxidant activity of the leaf extract from the medicinal halophyteThespesia populneareveal a potential source of bioactive compounds and nutraceuticals

“…Furthermore, the T. populnea leaf contained epigallocatechin gallate and naringenin in significant amounts. These two compounds have been reported for their antioxidant, antiproliferative, and antidiabetic activities (Franko et al, ). Besides these, other pharmaceutically important polyphenols like gentisic acid, syringic acid, rutin, ellagic acid, sinapic acid, resveratrol, salicylic acid, quercetin, coumarin, cinnamic acid, and apigenin were also identified in the T. populnea leaf (Table ).…”

Zinc Boosts EGCG’s hIAPP Amyloid Inhibition Both in Solution and Membrane

“…NMR spectra showed line broadening of amide-proton resonances of hIAPP in the presence of EGCG (Fig.S7), which is in agreement with a recent NMR study. [12] As EGCG aggregates were detected by DLS measurements (Fig.S4) and photography (Fig.S7, right panel), binding of hIAPP (ITC analyses in Fig. 4) to EGCG aggregates was ascribed to line broadending.…”

“…A recent study reported morphologically distinct hIAPP aggregates in the presence of EGCG and suggested interactions between hIAPP and EGCG at the atomistic resolution. [12] Thus, to further characterize effects of Zn(II) on intermolecular interactions and phase states of EGCG as well as on hIAPP amyloid aggregation, we performed a series of one-dimensional proton NMR measurements (Fig. S7, left).…”

“…Indeed, other metal ions such as aluminum have also shown to enhance the antiamyloidogenic property of EGCG due to complex formation and aggregation. [12] Oligomers of 5,5,6,6-tetrachloro-1,1,3,3-tetraethylbenzimidazolylcarbocyanine iodide (JC-1), a fluorescent dye, bound to alpha-synuclein [24] and oligomers of polyphenolic compounds including EGCG and catechin exhibited higher potency to suppress amyloid fibrillation of amyloid-b and insulin than their monomeric forms. [25,26] Collectively, aggregated forms of EGCG:Zn(II) complex are expected to be excellent in inhibiting hIAPP amyloidogenesis in a more efficient way than EGCG by using better binding ability for hIAPP in terms of the binding affinity and the number of bound molecules as revealed in ITC analyses.…”

“…[7] One of the frequently investigated amyloid inhibitors is epigallocatechin-gallate (EGCG; the major catechin present in green tea) ( Fig.S1B), a polyphenolic compound found in green tea extract. [8][9][10][11][12] EGCG has been shown to be an effective amyloid inhibitor for a variety of amyloid-forming peptides and proteins. In addition to small molecule modulation, metal ions were shown to play a role in amyloid aggregation.…”