调节分子对β淀粉样蛋白的聚集调控及细胞毒性抑制效应

Regulation of Aggregation and Cytotoxicity of β-Amyloid by Molecular Modulators

β淀粉样蛋白（β-amyloid protein,Aβ）在阿尔兹海默病的发生发展过程中起着关键作用。Aβ在体内可以由单体聚集成寡聚体及多种不同尺度的中间体,最终形成纤维,沉积在神经细胞外部形成淀粉样斑块,导致神经细胞功能障碍或者死亡。其中,球形寡聚体或者小的纤维聚集体被认为可能是产生细胞毒性的主要原因。与Aβ具有特定相互作用的小分子可以对Aβ聚集的动力学过程产生显著影响,从而抑制其细胞毒性,有关的研究工作可以归纳为两个方面：抑制Aβ的聚集从而减少毒性聚集体的产生,或者加速Aβ的聚集从而快速、有效地降低有毒多肽聚集体的浓度和存在时间。研究表明,染料及其类似物、离子螯合剂、多肽分子、吡啶类有机小分子等多种调节分子,可以与Aβ单体或各级组装体进行相互作用,从而实现对聚集过程及细胞毒性的调控。研究调节分子与Aβ的相互作用有助于阐明Aβ的聚集及相关神经毒性的机制,并为阿尔兹海默病的预防、药物设计和治疗提供新的思路。

β-amyloid（Aβ） is crucial to the pathogenesis of Alzheimer＇s disease.Aβ molecules self-assemble hierarchically and form a variety of intermediates and mature fibers,which result in neuron dysfunction and death.Spherical oligomers or protofibrillar aggregates are thought to be the primary neurotoxins.A range of small molecules that have been demonstrated to interact with monomer,oligomeric or fibrillar forms of Aβ could modulate Aβ aggregation process and reduce cytotoxicity.The strategies can be specified into two categories,one is the inhibition of aggregation for protecting neurons against Aβ toxicity and another is the acceleration of aggregation to decrease the concentration and life of toxic peptide aggregates rapidly and efficiently for neuron protection effect.It is demonstrated that stains and their analogues,metal ion chelators,short peptides and pyridyl organic molecules could interact with Aβ monomers or intermediates and modulate Aβ aggregation process and cytoxicity.These studies about interactions between molecular modulators and Aβ may help elucidate the mechanism of Aβ aggregation and neurotoxicity and provide a venue for designing diagnostic and therapeutic reagents.