Mechanistic insights into the inhibition of amyloid-β aggregation by chitosan
Mechanistic insights into the inhibition of amyloid-β aggregation by chitosan
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DOI：
10.1039/d3cp00162h
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发表时间：
2023-03-22
影响因子：
3.3
通讯作者：
Matysiak, Silvina
中科院分区：
文献类型：
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作者：
Gotla, Suhas;Matysiak, Silvina
与阿尔茨海默病相关的神经变性长期以来一直与淀粉样β（A β）肽异常聚集体的积累有关。A β聚集的前纤维状低聚中间体被认为是神经毒性的主要驱动因素，然而，它们的靶向仍然是一个未解决的挑战。作为响应，血脑屏障的大分子组分、人工细胞外基质模拟物和聚合物药物递送颗粒对A β肽聚集的影响正引起人们的兴趣。多项实验研究已经证明了一种这样的大分子，壳聚糖（CHT）-一种具有酸诱导阳离子性（pK（a）6.5）的多糖-抑制A β聚集并降低相关神经毒性作用的潜力。然而，这种抑制作用的机制细节，以及新兴的A β复合物的结构细节尚不清楚。在这项工作中，我们使用粗粒度的分子动力学模拟来探索CHT如何调节A β的中心疏水核心片段K（16）LVFFAE（22）的聚集。发现CHT结合并螯合A β肽，从而限制它们的最终聚集数。这种抑制作用的强度增强CHT浓度，以及CHT的pH依赖性程度的阳离子性，证实了实验观察。此外，发现CHT重塑A β肽的构象景观，在pH 7.5的近生理条件下富集塌陷的肽，在pH 6.5的微酸性条件下富集延伸的肽，其中K（16）LVFFAE（22）肽的电荷分布保持不变。这些构象变化仅限于在CHT中直接接触的肽，从而强调了局部环境对A β构象的影响。这些发现增加了A β肽聚集行为的基础知识，并可能指导开发用于治疗阿尔茨海默病的先进的基于CHT的材料。
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.