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S100 pro-inflammatory cytokines, particularly S100B, are activated during AD, but recent findings reveal an unconventional molecular chaperone role for S100B in hindering A\u03b2 aggregation and toxicity. This suggests a potential protective role for S100B at the onset of A\u03b2 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 A\u03b2 aggregation kinetics indicated that oxidized S100B was more effective in preventing aggregation, potentially linked to the oxidation of Met residues within the S100:A\u03b2 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 A\u03b2 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-\u03b12 expression as mediated by S100B.<\/jats:p>","DOI":"10.3390\/ijms25031787","type":"journal-article","created":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T08:44:08Z","timestamp":1706777048000},"page":"1787","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Secondary Modification of S100B Influences Anti Amyloid-\u03b2 Aggregation Activity and Alzheimer\u2019s Disease Pathology"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9791-1422","authenticated-orcid":false,"given":"Romina","family":"Coelho","sequence":"first","affiliation":[{"name":"BioISI\u2014Instituto de Biosistemas e Ci\u00eancias Integrativas, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"},{"name":"Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"}]},{"given":"Chiara A.","family":"De Benedictis","sequence":"additional","affiliation":[{"name":"Cellular Neurobiology and Neuro-Nanotechnology Laboratory, Department of Biological Sciences, University of Limerick, V94PH61 Limerick, Ireland"},{"name":"Bernal Institute, University of Limerick, V94PH61 Limerick, Ireland"}]},{"given":"Ann Katrin","family":"Sauer","sequence":"additional","affiliation":[{"name":"Cellular Neurobiology and Neuro-Nanotechnology Laboratory, Department of Biological Sciences, University of Limerick, V94PH61 Limerick, Ireland"},{"name":"Bernal Institute, University of Limerick, V94PH61 Limerick, Ireland"},{"name":"Health Research Institute (HRI), University of Limerick, V94PH61 Limerick, Ireland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4869-9335","authenticated-orcid":false,"given":"Ant\u00f3nio J.","family":"Figueira","sequence":"additional","affiliation":[{"name":"BioISI\u2014Instituto de Biosistemas e Ci\u00eancias Integrativas, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"},{"name":"Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0378-3624","authenticated-orcid":false,"given":"H\u00e9lio","family":"Faustino","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, 1649-003 Lisboa, Portugal"},{"name":"Association BLC3\u2014Technology and Innovation Campus, Centre Bio R&D Unit, Oliveira do Hospital, Rua Nossa Senhora da Concei\u00e7\u00e3o No. 2, 3405-155 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0005-4810","authenticated-orcid":false,"given":"Andreas M.","family":"Grabrucker","sequence":"additional","affiliation":[{"name":"Cellular Neurobiology and Neuro-Nanotechnology Laboratory, Department of Biological Sciences, University of Limerick, V94PH61 Limerick, Ireland"},{"name":"Bernal Institute, University of Limerick, V94PH61 Limerick, Ireland"},{"name":"Health Research Institute (HRI), University of Limerick, V94PH61 Limerick, Ireland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4662-6933","authenticated-orcid":false,"given":"Cl\u00e1udio M.","family":"Gomes","sequence":"additional","affiliation":[{"name":"BioISI\u2014Instituto de Biosistemas e Ci\u00eancias Integrativas, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"},{"name":"Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nature12481","article-title":"Self-propagation of pathogenic protein aggregates in neurodegenerative diseases","volume":"501","author":"Jucker","year":"2013","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1038\/nm1066","article-title":"Protein aggregation and neurodegenerative disease","volume":"10","author":"Ross","year":"2004","journal-title":"Nat. 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