Amyloid formation is a widespread phenomenon based on the generic property of the polypeptide chain to self-assemble into a cross-β-sheet containing oligomers and fibrils. Their growth and accumulation are manifested in numerous amyloid-related diseases, including neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. We consider the effect of cyclic compounds and their conjugates on the amyloid formation of pro-inflammatory S100A9 protein, which was found to be a common denominator in Alzheimer’s and Parkinson’s disease as well as in traumatic brain injury, which is considered as a pre-cursor state for neurodegenerative ailments. Indeed, amyloid formation is commonly associated with neuroinflammation, and pro-inflammatory S100A9 protein acts both as an alarmin, inducing the production of pro-inflammatory cytokines, and as a highly amyloidogenic protein, which self-assembles into amyloids under physiological conditions.
The amyloid cascade is central for the neurodegeneration disease pathology, including Alzheimer’s and Parkinson’s, and remains the focus of much current research. S100A9 protein drives the amyloid-neuroinflammatory cascade in these diseases. DOPA and cyclen-based compounds were used as amyloid modifiers and inhibitors previously, and DOPA is also used as a precursor of dopamine in Parkinson’s treatment. Here, by using fluorescence titration experiments we showed that five selected ligands: DOPA-D-H-DOPA, DOPA-H-H-DOPA, DOPA-D-H, DOPA-cyclen, and H-E-cyclen, bind to S100A9 with apparent Kd in the sub-micromolar range. Ligand docking and molecular dynamic simulation showed that all compounds bind to S100A9 in more than one binding site and with different ligand mobility and H-bonds involved in each site, which all together is consistent with the apparent binding determined in fluorescence experiments. By using amyloid kinetic analysis, monitored by thioflavin-T fluorescence, and AFM imaging, we found that S100A9 co-aggregation with these compounds does not hinder amyloid formation but leads to morphological changes in the amyloid fibrils, manifested in fibril thickening. Thicker fibrils were not observed upon fibrillation of S100A9 alone and may influence the amyloid tissue propagation and modulate S100A9 amyloid assembly as part of the amyloid-neuroinflammatory cascade in neurodegenerative diseases. . Even though amyloid development in the brain tissues could be the primary target for DOPA-based compounds, and therefore, here, we studied their interactions with S100A9, it remains an open possibility that in some other functional or pathological conditions in other organ and tissues than the brain, binding of DOPA and cyclen-based compounds to S100A9 may affect its interaction and co-aggregation with S100A8.

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