Secondary Modification of S100B Influences Anti Amyloid-β Aggregation Activity and Alzheimer’s Disease Pathology

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Abstract
Proteinaceous aggregates accumulate in neurodegenerative diseases such as Alzheimer’s Disease (AD), inducing cellular defense mechanisms and altering the redox status. S100 pro-inflammatory cytokines, particularly S100B, are activated during AD, but recent findings reveal an unconventional molecular chaperone role for S100B in hindering Aβ aggregation and toxicity. This suggests a potential protective role for S100B at the onset of Aβ proteotoxicity, occurring in a complex biochemical environment prone to oxidative damage. Herein, we report an investigation in which extracellular oxidative conditions are mimicked to test if the susceptibility of S100B to oxidation influences its protective activities. Resorting to mild oxidation of S100B, we observed methionine oxidation as inferred from mass spectrometry, but no cysteine-mediated crosslinking. Structural analysis showed that the folding, structure, and stability of oxidized S100B were not affected, and nor was its quaternary structure. However, studies on Aβ aggregation kinetics indicated that oxidized S100B was more effective in preventing aggregation, potentially linked to the oxidation of Met residues within the S100:Aβ binding cleft that favors interactions. Using a cell culture model to analyze the S100B functions in a highly oxidative milieu, as in AD, we observed that Aβ toxicity is rescued by the co-administration of oxidized S100B to a greater extent than by S100B. Additionally, results suggest a disrupted positive feedback loop involving S100B which is caused by its oxidation, leading to the downstream regulation of IL-17 and IFN-α2 expression as mediated by S100B.
Funding Information
  • Fundação para a Ciência e Tecnologia (Portugal) (SFRH/PD/BD/142897/2018, BD/06393/2021, UIDB/04046/2020, UIDP/MULTI/04046/2020, GA 101079147)
  • European Union (SFRH/PD/BD/142897/2018, BD/06393/2021, UIDB/04046/2020, UIDP/MULTI/04046/2020, GA 101079147)

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