Effects of Charged Polyelectrolytes on Amyloid Fibril Formation of a Tau Fragment

Abstract

The microtubule-associated protein tau is involved in more than 20 different neurological disorders characterized by aberrant intracellular aggregation of tau in the brain. Here, we investigated the aggregation of a novel 20-residue model peptide, tau298–317, which is derived from the key microtubule binding domain of the full sequence tau. Our results show that tau298–317 highly mimics the physical and aggregation properties of tau. Under normal physiological conditions, the peptide maintains a disordered random coil without aggregation. 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 and the introduction of the negatively charged phosphate group on a serine (Ser305) residue in the sequence, 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), were found to 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. Our results suggest that positively charged polyelectrolytes with optimized charged groups and charge distribution patterns can serve as effective molecular candidates to block tau–Hep interactions and prevent aggregation of tau induced by Hep and other polyanions.

Mechanistic insights into the inhibition of amyloid-β aggregation by chitosan

“…This finding of locus-dependent heterogeneity in Ab conformations offers some insight into why CHT inhibits amyloid aggregation while other polysaccharides, particularly those of the anionic glycosaminoglycan family, strongly induce the formation of ordered amyloid fibrils. 10,[35][36][37] Further studies aimed at delineating the effects of different polysaccharides on amyloid aggregation are planned.…”