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The aggregates can diffuse within brain areas, and their toxicity has been proven in both cellular and animal models. Given that, recent therapeutic strategies have been focusing on the identification of compounds able to promote the degradation of aggregates or, at least, to prevent the aggregation process. In this field, the use of natural-derived polyphenols has been proposed as a potential tool against \u03b1-synuclein pathology. On these bases, we tested the neuroprotective potential of oleuropein aglycone, an olive polyphenol, in two cellular and\n                    <jats:italic>C. elegans<\/jats:italic>\n                    \u2013based models of Parkinson\u2019s disease. The compound was effective in reducing the burden of early-aggregates pathology upon \u03b1-synuclein overexpression in neuroblastoma cells, as well as neutralizing both the extent and the toxicity of administered preformed fibrils. In addition, oleuropein aglycone administration was beneficial for healthspan and lifespan in animals overexpressing \u03b1-synuclein, improved motor defects, recovered dopaminergic neuronal loss, and reduced the extent of \u03b1-synuclein pathology. Finally, through molecular modelling simulations, we propose a model for the \u03b1-synuclein and oleuropein aglycone interaction, predicting a dynamic that involves early \u03b1-synuclein oligomers. Overall, our results support the neuroprotective potential of oleuropein aglycone against \u03b1-synuclein aggregation and toxicity and shed light into the molecular features of these mechanisms, suggesting that further studies should be performed to gain insight about the neuroprotective actions of this polyphenol in humans.\n                  <\/jats:p>","DOI":"10.1007\/s12035-025-05208-6","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T00:58:43Z","timestamp":1753318723000},"page":"15741-15758","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Oleuropein Aglycone, an Olive Polyphenol, Influences Alpha-Synuclein Aggregation and Exerts Neuroprotective Effects in Different Parkinson\u2019s Disease Models"],"prefix":"10.1007","volume":"62","author":[{"given":"Milo J.","family":"Basellini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 M.","family":"Granadino-Rold\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo V.","family":"Torres-Ortega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Simmini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime","family":"Rubio-Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Marin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graziella","family":"Cappelletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Cascante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Ca\u00f1uelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,24]]},"reference":[{"key":"5208_CR1","doi-asserted-by":"publisher","unstructured":"Chen X, de Silva HA, Pettenati MJ, Rao PN, St George-Hyslop P, Roses AD, Xia Y, Horsburgh K et al (1995) The human NACP\/alpha-synuclein gene: chromosome assignment to 4q21.3-q22 and TaqI RFLP analysis. 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