Correlation between Sialylation Status and Cell Susceptibility to Amyloid Toxicity

Abstract

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.

Development and evaluation of multi‐functionalized sialic acid conjugated asiatic acid nanoconstruct to mitigate cognitive deficits in Alzheimer's disease

“…It's also been shown that cell lines with high levels of SA are more vulnerable to Aβ toxicity. This toxicity may cause a change in neuron metabolism, resulting in a reparative rise in SA, which may favor amyloid binding to GM1, aggravating cell dysmetabolism and promoting more amyloid aggregation (Bucciantini et al, 2012; Sgambati et al, 2022a). Being a chief ligand for microglial Siglecs, an immunoglobulin‐type lectins (sialoadhesin), it holds a critical role in microglial homeostasis in the healthy brain (Li et al, 2021; Rawal & Zhao, 2021; Sundaram, 2017; Tosi et al, 2010; Wo et al, 2017; Xu et al, 2020).…”

“…SA levels are found highest in brain endothelial cells where it functions as an important regulator of neurogenesis, neuronal repair and remodeling. SA is a possible contender for inhibiting Aβ aggregation and decreasing neuroinflammatory responses through sialylation, which improves Aβ interaction, cellular internalization, and transport through the brain by endorsing their binding with the GM1 ganglioside receptor (Bucciantini et al, 2012; Gallart‐Palau et al, 2021; Sgambati et al, 2022a; 2022b; Sundaram, 2017). AA was also found to be the most effective (97%) and potent against Aβ neurotoxicity.…”

The Surprising Nonlinear Effects of S100A9 Proteins in the Retina

“…Various amyloids can distinctively affect different cell types, with the effects of fibrils specifically linked to their interaction with plasma membrane ligands and binding to lipid-rafts on the cell surface . For example, a significant inverse relation was observed between the membrane cholesterol content and the cellular damage inflicted by amyloids, and cells with a neuron-like phenotype and high levels of sialic acid in the cell membrane were particularly susceptible to amyloids such as Aβ . Thus, different cell types manifesting varying compositions and levels of plasma membrane receptors and displaying different surface properties can alter susceptibility to amyloids.…”