Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, Pesche, 86090 Isernia, Italy.
Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
Cells. 2022 Feb 9;11(4):601. doi: 10.3390/cells11040601.
The interaction between the cell membrane and misfolded protein species plays a crucial role in the development of neurodegeneration. This study was designed to clarify the relationship between plasma membrane composition in terms of the differently linked sialic acid (Sia) content and cell susceptibility to toxic and misfolded Aβ-42 peptides. The sialylation status in different cell lines was investigated by lectin histochemistry and confocal immunofluorescence and then correlated with the different propensities to bind amyloid fibrils and with the relative cell susceptibility to amyloid damage. This study reveals that expressions of Sias α2,3 and α2,6 linked to galactose/N-acetyl-galactosamine, and PolySia are positively correlated with Aβ-42-induced cell toxicity. PolySia shows an early strong interaction with amyloid fibrils, favoring their binding to GM1 ganglioside containing α2,3 galactose-linked Sia and a loss of cell viability. Our findings demonstrate that cell lines with a prevailing plastic neuron-like phenotype and high monoSia and PolySia contents are highly susceptible to amyloid Aβ-42 toxicity. This toxicity may involve a change in neuron metabolism and promote a compensative/protective increase in PolySia, which, in turn, could favor amyloid binding to GM1, thus exacerbating cell dysmetabolism and further amyloid aggregation.
细胞膜与错误折叠蛋白的相互作用在神经退行性变的发展中起着至关重要的作用。本研究旨在阐明细胞膜组成与毒性和错误折叠的 Aβ-42 肽的细胞易感性之间的关系，具体表现在不同连接的唾液酸（Sia）含量方面。通过凝集素组织化学和共聚焦免疫荧光研究了不同细胞系中的唾液酸化状态，并将其与结合淀粉样纤维的不同倾向以及相对的细胞对淀粉样损伤的敏感性相关联。本研究揭示，与半乳糖/N-乙酰半乳糖胺连接的 Sia α2,3 和 α2,6 以及多聚唾液酸的表达与 Aβ-42 诱导的细胞毒性呈正相关。多聚唾液酸与淀粉样纤维早期有强烈的相互作用，有利于它们与含有α2,3 半乳糖连接的唾液酸的 GM1 神经节苷脂结合，并导致细胞活力丧失。我们的研究结果表明，具有占主导地位的可塑性神经元样表型和高单唾液酸和多聚唾液酸含量的细胞系对淀粉样 Aβ-42 毒性非常敏感。这种毒性可能涉及神经元代谢的变化，并促进多聚唾液酸的代偿/保护增加，这反过来又有利于淀粉样纤维与 GM1 的结合，从而加剧细胞代谢紊乱和进一步的淀粉样纤维聚集。
