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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,6,18]]},"abstract":"<jats:p>\n                    Shear forces affect self-assembly processes ranging from crystallization to fiber formation. Here, the effect of mild agitation on amyloid fibril formation was explored for four peptides and investigated in detail for A\n                    <jats:inline-formula>\n                      <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" display=\"inline\" overflow=\"scroll\">\n                        <mml:mrow>\n                          <mml:mi mathvariant=\"bold\">\u03b2<\/mml:mi>\n                        <\/mml:mrow>\n                      <\/mml:math>\n                    <\/jats:inline-formula>\n                    42, which is associated with Alzheimer\u2019s disease. To gain mechanistic insights into the effect of mild agitation, nonseeded and seeded aggregation reactions were set up at various peptide concentrations with and without an inhibitor. First, an effect on fibril fragmentation was excluded by comparing the monomer-concentration dependence of aggregation kinetics under idle and agitated conditions. Second, using a secondary nucleation inhibitor, Brichos, the agitation effect on primary nucleation was decoupled from secondary nucleation. Third, an effect on secondary nucleation was established in the absence of inhibitor. Fourth, an effect on elongation was excluded by comparing the seeding potency of fibrils formed under idle or agitated conditions. We find that both primary and secondary nucleation steps are accelerated by gentle agitation. The increased shear forces facilitate both the detachment of newly formed aggregates from catalytic surfaces and the rate at which molecules are transported in the bulk solution to encounter nucleation sites on the fibril and other surfaces. Ultrastructural evidence obtained with cryogenic transmission electron microscopy and free-flow electrophoresis in microfluidics devices imply that agitation speeds up the detachment of nucleated species from the fibril surface. Our findings shed light on the aggregation mechanism and the role of detachment for efficient secondary nucleation. The results inform on how to modulate the relative importance of different microscopic steps in drug discovery and investigations.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2322572121","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T13:00:31Z","timestamp":1718370031000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":43,"title":["The role of shear forces in primary and secondary nucleation of amyloid fibrils"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5687-9566","authenticated-orcid":false,"given":"Emil","family":"Axell","sequence":"first","affiliation":[{"name":"Biochemistry and Structural Biology, Department of Chemistry, Lund University, SE-221 00 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3605-2185","authenticated-orcid":false,"given":"Jing","family":"Hu","sequence":"additional","affiliation":[{"name":"Division of Physical Chemistry, Department of Chemistry, Lund University, SE-221 00 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1579-4970","authenticated-orcid":false,"given":"Max","family":"Lindberg","sequence":"additional","affiliation":[{"name":"Biochemistry and Structural Biology, Department of Chemistry, Lund University, SE-221 00 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3055-607X","authenticated-orcid":false,"given":"Alexander J.","family":"Dear","sequence":"additional","affiliation":[{"name":"Biochemistry and Structural Biology, Department of Chemistry, Lund University, SE-221 00 Lund, Sweden"},{"name":"Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, Cambridge University, CB2 1EW Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0656-9225","authenticated-orcid":false,"given":"Lei","family":"Ortigosa-Pascual","sequence":"additional","affiliation":[{"name":"Biochemistry and Structural Biology, Department of Chemistry, Lund University, SE-221 00 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa A.","family":"Andrzejewska","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, Cambridge University, CB2 1EW Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4585-5091","authenticated-orcid":false,"given":"Greta","family":"\u0160neiderien\u0117","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, Cambridge University, CB2 1EW Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6171-9703","authenticated-orcid":false,"given":"Dev","family":"Thacker","sequence":"additional","affiliation":[{"name":"Biochemistry and Structural Biology, Department of Chemistry, Lund University, SE-221 00 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7879-0140","authenticated-orcid":false,"given":"Tuomas P. 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