Aggregation of misfolded oligomeric amyloid-beta (Aβ) peptides on lipid membranes has been identified as a primary event in Alzheimer's pathogenesis. However, the structural and dynamical features of this membrane assisted Aβ aggregation have not been well characterized. The microscopic characterization of dynamic molecular-level interactions in peptide aggregation pathways has been challenging both computationally and experimentally. In this work, we explore differential patterns of membrane-induced Aβ 16–22 (K–L–V–F–F–A–E) aggregation from the microscopic perspective of molecular interactions. Physics-based coarse-grained molecular dynamics (CG-MD) simulations were employed to investigate the effect of lipid headgroup charge – zwitterionic (1-palmitoyl-2-oleoyl- sn-glycero -3-phosphocholine: POPC) and anionic (1-palmitoyl-2-oleoyl- sn-glycero -3-phospho- l -serine: POPS) – on Aβ 16–22 peptide aggregation. Our analyses present an extensive overview of multiple pathways for peptide absorption and biomechanical forces governing peptide folding and aggregation. In agreement with experimental observations, anionic POPS molecules promote extended configurations in Aβ peptides that contribute towards faster emergence of ordered β-sheet-rich peptide assemblies compared to POPC, suggesting faster fibrillation. In addition, lower cumulative rates of peptide aggregation in POPS due to higher peptide–lipid interactions and slower lipid diffusion result in multiple distinct ordered peptide aggregates that can serve as nucleation seeds for subsequent Aβ aggregation. This study provides an in-silico assessment of experimentally observed aggregation patterns, presents new morphological insights and highlights the importance of lipid headgroup chemistry in modulating the peptide absorption and aggregation process.
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Mechanistic insights into the inhibition of amyloid-β aggregation by chitosan
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 (p K a 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, K 16 LVFFAE 22 , 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 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 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.
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- Award ID(s):
- 2202281
- NSF-PAR ID:
- 10412401
- Date Published:
- Journal Name:
- Physical Chemistry Chemical Physics
- Volume:
- 25
- Issue:
- 14
- ISSN:
- 1463-9076
- Page Range / eLocation ID:
- 10113 to 10120
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D3CP00162H
