Differential inhibition of metabolite amyloid formation by generic fibrillation-modifying polyphenols

Abstract

The formation of ordered amyloid fibrils by proteins and polypeptides is associated with human disorders. A recent extension of the amyloidogenic building block family includes several small metabolites, which form assemblies with structural and functional similarities to well-established amyloids. Here we investigate whether generic amyloid polyphenolic inhibitors can also restrict the formation of metabolite fibrils. We reveal that epigallocatechin gallate and tannic acid inhibit amyloid-like fibrillation of adenine, phenylalanine, and tyrosine. Moreover, the compounds reduce the cytotoxicity triggered by these assemblies. In contrast, acetylsalicylic acid, used as a control does not have an inhibitory effect. The compounds' differential effects at various time points is consistent with molecular dynamics simulations, providing information about the inhibition mechanisms and inhibitors' key interactions with the monomeric and subsequent crystalline fibril states. Taken together, we provide additional evidence for the fundamental similarities between protein-and metabolite-based amyloids, the inhibition process and dynamics of association.

Antioxidant Nanoparticles for Concerted Inhibition of α-Synuclein Fibrillization, and Attenuation of Microglial Intracellular Aggregation and Activation

“…While previous research has shown that tannic acid can reduce the production of neuroinflammatory factors such as ROS, NO and TNF-α from LPS-treated microglia via the suppression of the NF-κB pathway, our results show that tannic acid only reduces intracellular ROS production but does not have an appreciable effect on the other two markers (Figures 5A-D; Wu et al, 2019). This could potentially suggest that the rate at which tannic acid associates with αSYN is much faster than its interaction with other signaling molecules involved in the pathway (Shaham-Niv et al, 2018). The only major inflammatory biomarker that was not appreciably modulated by the [FAA:TA] NPs was IL-6 production from LPSprimed microglia ( Figure 5D).…”

Antibodies towards Tyrosine Amyloid-Like Fibrils Allow Toxicity Modulation and Cellular Imaging of the Assemblies

“…Tannic acid (TA) and epigallocatechin gallate (EGCG), are two polyphenolic compounds previously shown to inhibit the self-assembly of proteinaceous amyloids [ 27 , 28 ] and recently demonstrated, using time-dependent ThT fluorescence assay, to hinder the Tyr self-assembly process [ 29 ]. Pre-treatment of the Tyr solution with either of the polyphenols hindered immune-recognition ( Figure 2 A-IV–V).…”

PrP (58–93) peptide from unstructured N-terminal domain of human prion protein forms amyloid-like fibrillar structures in the presence of Zn2+ ions

“…Insoluble brillar polypeptide structures appear as a result of a misfolding process in numerous proteins or peptides and accompany the amyloid aggregation process. [1][2][3][4][5][6] The most spectacular structures of this type are linked to the development of fatal neurodegenerative disorders such as Alzheimer's disease, 7,8 Icelandic type amyloidosis 9,10 or Creutzfeldt-Jakob disease. 11,12 The latter belongs to the group of diseases called transmissible spongiform encephalopathies (TSE) in which a misfolding of human prion protein (PrP) is responsible for the formation of brillar aggregates in the brain.…”