Amyloidogenecity of the Peptide Fragment in Microtubule Binding Repeat Domain of Tau

Majedul Islam, Deguo Du

Florida Atlantic University

Understanding the mechanistic details of tau aggregation is critical for unraveling the underlying pathology of tauopathies and developing effective strategies to inhibit tau aggregation. Herein, we investigated the aggregation of a novel 20-residue model peptide, tau₂₉₈₋₃₁₇, derived from the key microtubule-binding domain of the full sequence tau. Our study demonstrates that tau₂₉₈₋₃₁₇ highly mimics full-length tau's physical and aggregation properties. The fibrillation of the peptide is strongly dependent on external factors and the presence of polyanionic heparin (Hep) significantly promotes the aggregation of this peptide to form amyloid fibrils. In addition, two positively charged polysaccharides, chitosan (CHT) and its quaternary derivative N-trimethyl chitosan (TMC), effectively inhibit Hep-induced aggregation of tau₂₉₈₋₃₁₇ in a concentration-dependent manner. Attractive electrostatic interactions between the positively charged moieties in CHT/TMC and the negatively charged residues of Hep play a critical role in inhibiting Hep–peptide interactions and suppressing peptide aggregation. Furthermore, we studied the effects of tau₂₉₈₋₃₁₇ and its mutants on membrane damage, and the impacts of palmitic acid on the peptide aggregation, providing mechanistic insight into aggregation of this crucial tau region in cell-mimicking environment.