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We investigated how A\u03b242 \u2013 the predominant A\u03b2 form in AD \u2013 co\u2010aggregates with four \u03b1Syn splice isoforms (\u03b1Syn\u2010140, \u03b1Syn\u2010126, \u03b1Syn\u2010112 and \u03b1Syn\u201098) implicated in PD, finding evidence of a two\u2010step process. A\u03b242 first aggregated into fibrillar assemblies, which then acted as potent nucleation surfaces for initiating the aggregation of \u03b1Syn isoforms. Furthermore, pre\u2010formed A\u03b242 seeds promoted \u03b1Syn aggregation more strongly than\n                      <jats:italic>in situ<\/jats:italic>\n                      A\u03b242 aggregates. Our results reveal a unified A\u03b2\u2013\u03b1Syn co\u2010aggregation mechanism, where A\u03b2 aggregation and \u03b1Syn splicing synergistically drive co\u2010deposition. These findings could help develop therapeutic tools to target key steps in disease\u2010related co\u2010aggregation pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"box\" position=\"anchor\">\n                        <jats:caption>\n                          <jats:title>Impact statement<\/jats:title>\n                        <\/jats:caption>\n                        <jats:p>By demonstrating that A\u03b242 fibril seeds serve as potent heterogeneous nucleation surfaces for four common \u03b1\u2010synuclein splice isoforms, this study mechanistically links protein aggregation in Alzheimer's and Parkinson's diseases. Kinetic analysis identifies early cross\u2010seeding events, suggesting intervention points to delay mixed amyloid pathologies in neurodegeneration.<\/jats:p>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/1873-3468.70118","type":"journal-article","created":{"date-parts":[[2025,7,26]],"date-time":"2025-07-26T07:34:45Z","timestamp":1753515285000},"page":"2750-2767","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A\u03b242 promotes the aggregation of \u03b1\u2010synuclein splice isoforms\n                    <i>via<\/i>\n                    heterogeneous nucleation"],"prefix":"10.1002","volume":"599","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0500-4815","authenticated-orcid":false,"given":"Alexander","family":"R\u00f6ntgen","sequence":"first","affiliation":[{"name":"Centre for Misfolding Diseases, Yusuf Hamied Department of 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