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

Neurodegeneration related to Alzheimer's disease has long been linked to the accumulation of abnormal aggregates of amyloid-beta (A beta) peptides. Pre-fibrillar oligomeric intermediates of A beta aggregation are considered the primary drivers of neurotoxicity, however, their targetting remains an unresolved challenge. In response, the effects of macromolecular components of the blood-brain barrier, artificial extracellular matrix mimics, and polymeric drug delivery particles, on the aggregation of A beta peptides are gaining interest. Multiple experimental studies have demonstrated the potential of one such macromolecule, chitosan (CHT) - a polysaccharide with acid induced cationicity (pK(a) 6.5) - to inhibit the aggregation of A beta, and reduce the associated neurotoxic effects. However, the mechanistic details of this inhibitory action, and the structural details of the emergent A beta complexes are not understood. In this work, we probed how CHT modulated the aggregation of A beta's central hydrophobic core fragment, K(16)LVFFAE(22), using coarse-grained molecular dynamics simulations. CHT was found to bind and sequester A beta peptides, thus limiting their ultimate aggregation numbers. The intensity of this inhibitory action was enhanced by CHT concentration, as well as CHT's pH-dependent degree of cationicity, corroborating experimental observations. Furthermore, CHT was found to reshape the conformational landscapes of A beta peptides, enriching collapsed peptides at near-physiological conditions of pH 7.5, and extended peptides at slightly acidic conditions of pH 6.5, where the charge profile of K(16)LVFFAE(22) peptides remained unchanged. These conformational changes were limited to peptides in direct contact in CHT, thus emphasizing the influence of local environments on A beta conformations. These findings add to basic knowledge of the aggregation behaviour of A beta peptides, and could potentially guide the development of advanced CHT-based materials for the treatment of Alzheimer's disease.