Issue 14, 2023

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

Abstract

Neurodegeneration related to Alzheimer's disease has long been linked to the accumulation of abnormal aggregates of amyloid-β (Aβ) peptides. Pre-fibrillar oligomeric intermediates of Aβ 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 Aβ peptides are gaining interest. Multiple experimental studies have demonstrated the potential of one such macromolecule, chitosan (CHT) – a polysaccharide with acid induced cationicity (pKa 6.5) – to inhibit the aggregation of Aβ, and reduce the associated neurotoxic effects. However, the mechanistic details of this inhibitory action, and the structural details of the emergent Aβ complexes are not understood. In this work, we probed how CHT modulated the aggregation of Aβ's central hydrophobic core fragment, K16LVFFAE22, using coarse-grained molecular dynamics simulations. CHT was found to bind and sequester Aβ 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 Aβ 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 K16LVFFAE22 peptides remained unchanged. These conformational changes were limited to peptides in direct contact in CHT, thus emphasizing the influence of local environments on Aβ conformations. These findings add to basic knowledge of the aggregation behaviour of Aβ peptides, and could potentially guide the development of advanced CHT-based materials for the treatment of Alzheimer's disease.

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

Supplementary files

Article information

Article type
Paper
Submitted
11 1月 2023
Accepted
22 3月 2023
First published
22 3月 2023

Phys. Chem. Chem. Phys., 2023,25, 10113-10120

Author version available

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

S. Gotla and S. Matysiak, Phys. Chem. Chem. Phys., 2023, 25, 10113 DOI: 10.1039/D3CP00162H

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