There is compelling evidence that small oligomeric aggregates, emerging during the assembly of amyloid fibrils and plaques, are important molecular pathogens in many amyloid diseases. While significant progress has been made in revealing the mechanisms underlying fibril growth, understanding how amyloid oligomers fit into the fibril assembly process, and how they contribute to the pathogenesis of amyloid diseases, has remained elusive. Commonly, amyloid oligomers are considered to be metastable, early-stage precursors to fibril formation that are either on- or off-pathway from fibril growth. In addition, amyloid oligomers have been reported to colocalize with late-stage fibrils and plaques. Whether these early and late-stage oligomer species are identical or distinct, and whether both are relevant to pathogenesis remains unclear. Here we report on the formation of two distinct oligomer species of lysozyme, formed either during the early or late-stages of in vitro fibril growth. We further observe that the pH change from in vitro growth conditions to cell media used for toxicity studies induced distinct mesoscopic precipitates, two of which resemble either diffuse or neuritic plaques seen in Alzheimer's histology. Our biophysical characterization indicates that both oligomer species share morphological and tinctorial features considered characteristic for amyloid oligomers. At the same time, their sizes, morphologies, their immunostaining, detailed tinctorial profiles and, most prominently, their biological activity are clearly distinct from each other. Probing the conditions promoting the formation of these two distinct oligomer species suggests distinct roles of charge interactions, hydrophobicity and monomer flexibility in directing oligomer assembly.

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两种淀粉样寡聚体多晶型物的来源、毒性及特性

有令人信服的证据表明，在淀粉样原纤维和斑块组装过程中出现的小寡聚体是许多淀粉样疾病的重要分子病原体。虽然在揭示原纤维生长的机制方面取得了重大进展，但了解淀粉样蛋白寡聚体如何适应原纤维组装过程，以及它们如何促进淀粉样蛋白疾病的发病机制，仍然难以捉摸。通常，淀粉样蛋白寡聚体被认为是原纤维形成的亚稳态、早期前体，它们在原纤维生长的通路或非通路中。此外，据报道淀粉样蛋白寡聚体与晚期原纤维和斑块共定位。这些早期和晚期寡聚体物种是相同的还是不同的，以及两者是否与发病机制有关仍不清楚。体外纤维生长。我们进一步观察到体外pH 值的变化用于毒性研究的细胞培养基的生长条件诱导了不同的细观沉淀物，其中两种类似于阿尔茨海默病组织学中的弥散斑块或神经炎斑块。我们的生物物理表征表明，这两种寡聚体都具有淀粉样寡聚体所认为的形态和着色特征。同时，它们的大小、形态、免疫染色、详细的着色特征以及最突出的生物活性彼此明显不同。探索促进这两种不同低聚物种类形成的条件表明电荷相互作用、疏水性和单体灵活性在指导低聚物组装中的不同作用。