AMYLOIDOGENICITY OF THE PEPTIDE FRAGMENT IN MICROTUBULE BINDING REPEAT DOMAIN OF TAU

Tau, a microtubule-associated protein, is involved in more than 20 different tauopathic disorders characterized by aberrant intracellular aggregation of tau in the brain. However, it is still unclear how this highly soluble tau protein aggregates inside the brain. Thus, 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. The presence of polyanionic heparin (Hep) significantly promotes the aggregation of this peptide to form amyloid fibrils. The Hep-induced aggregation is sensitive to the ionic strength of the solution, suggesting an important role of electrostatic interactions in the mechanism of Hep-mediated aggregation. 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.