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Metal ion dyshomeostasis plays an important role in diseases, including neurodegeneration. Tau protein is a known neurodegeneration biomarker, but its interactions with biologically relevant metal ions, such as Cu(II), are not fully understood. Herein, the Cu(II) complexes of four tau R peptides, based on the tau repeat domains, R1, R2, R3, and R4, were characterized by electrochemical methods, including cyclic voltammetry, square-wave voltammetry, and differential pulse voltammetry in solution under aerobic conditions. The current and potential associated with Cu(II)/(I) redox couple was modulated as a function of R peptide sequence and concentration. All R peptides coordinated Cu(II) resulting in a dramatic decrease in the current associated with free Cu(II), and the appearance of a new redox couple due to metallo–peptide complex. The metallo–peptide complexes were characterized by the irreversible redox couple at more positive potentials and slower electron-transfer rates compared with the free Cu(II). The competition binding studies between R peptides with Cu(II) indicated that the strongest binding affinity was observed for the R3 peptide, which contained 2 His and 1 Cys residues. The formation of complexes was also evaluated as a function of peptide concentration and in the presence of competing Zn(II) ions. Data indicate that all metallo–peptides remain redox active pointing to the potential importance of the interactions between tau protein with metal ions in a biological setting.

Gelsolin amyloidosis is a disease characterized by several point mutations that lead to cleavage and fibrillization of gelsolin. The D187 mutation to N or Y leads to aggregation of peptide fragments with shortest aggregating peptide identified as 182SFNNGDCFILD192. Recently, G167 has also been identified as relevant gelsolin mutation, which leads to gelsolin deposits in kidneys but its aggregation is much less understood. Hence, we systematically investigated in vitro the aggregation propensities of the following gelsolin peptides: 167GRRVV171, 161RLFQVKG167, 184NNGDCFILDL193, 188CFILDL193, 187DCFILDL193, and their respective mutants (G167K, G167R, N184K, D187Y, D187N), by using spectroscopic methods (fluorescence proteostat, Thioflavin T (ThT), turbidity assay, and Dynamic Light Scattering (DLS)), and Transmission Electron Microscopy (TEM). The (non) mutant peptides containing CFILDL sequence aggregated into fibrillar networks, while G167R mutation promoted aggregation compared to the wild‐type sequence. In the presence of inhibitors, Methylene Blue (MB) and Epigallocatechin gallate (EGCG), the gelsolin peptide aggregation was reduced. We discovered that inhibitors have dual functionality, as aggregation inhibitors and disaggregation promoters, potentially allowing for the prevention and reversal of gelsolin amyloidosis. Such therapeutic strategies may significantly improve outcomes related to other amyloidogenic diseases of the heart, brain and eye.