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The first is characterized by hyperphosphorylated tau protein and A\u03b2 peptide deposition, thus forming intracellular neurofibrillary tangles and extracellular senile plaques, respectively; while, in PD, \u03b1-synuclein aggregates and deposits as Lewy bodies. Considerable research has focused on developing protein aggregation models to be explored as research tools. In the present work, four in vitro models for studying protein aggregation were studied and compared, namely treatment with: the toxic A\u03b21-42 peptide, the isoflavone rotenone, the ATP synthase inhibitor oligomycin, and the proteosome inhibitor MG-132. All treatments result in aggregation-relevant events in the human neural SH-SY5Y cell line, but significant model-dependent differences were observed. In terms of promoting aggregate formation, A\u03b2 and MG-132 provoked the greatest effect, but only MG-132 was associated with an increase in HSP-70 chaperone expression. In fact, the type of aggregates formed appear to be dependent on the treatment employed, and supports the hypothesis that A\u03b2 exposure is a relevant AD model, and rotenone is a valid model for PD. Furthermore, the results revealed that protein phosphorylation is relevant to aggregate formation and as expected, tau co-localized to the deposits formed in the A\u03b2 peptide aggregate induction cell model. In summary, different molecular processes, from overall and specific protein aggregation to proteostatic modulation, can be induced by using distinct aggregation modelling strategies, and these can be used to study different protein-aggregation-related processes associated with distinct neuropathologies.<\/jats:p>","DOI":"10.1007\/s10571-025-01539-z","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T01:46:02Z","timestamp":1741830362000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Comparing In vitro Protein Aggregation Modelling Using Strategies Relevant to Neuropathologies"],"prefix":"10.1007","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1622-2268","authenticated-orcid":false,"given":"Andr\u00e9","family":"Nadais","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1946-8159","authenticated-orcid":false,"given":"In\u00eas","family":"Martins","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0851-6979","authenticated-orcid":false,"given":"Ana Gabriela","family":"Henriques","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4432-0925","authenticated-orcid":false,"given":"Diogo","family":"Trigo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3718-9874","authenticated-orcid":false,"given":"Odete A. 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