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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,5,23]]},"abstract":"<jats:p>Neurodegenerative diseases, such as Alzheimer\u2019s disease (AD), are associated with protein misfolding and aggregation into amyloid fibrils. Increasing evidence suggests that soluble, low-molecular-weight aggregates play a key role in disease-associated toxicity. Within this population of aggregates, closed-loop pore-like structures have been observed for a variety of amyloid systems, and their presence in brain tissues is associated with high levels of neuropathology. However, their mechanism of formation and relationship with mature fibrils have largely remained challenging to elucidate. Here, we use atomic force microscopy and statistical theory of biopolymers to characterize amyloid ring structures derived from the brains of AD patients. We analyze the bending fluctuations of protofibrils and show that the process of loop formation is governed by the mechanical properties of their chains. We conclude that ex vivo protofibril chains possess greater flexibility than that imparted by hydrogen-bonded networks characteristic of mature amyloid fibrils, such that they are able to form end-to-end connections. These results explain the diversity in the structures formed from protein aggregation and shed light on the links between early forms of flexible ring-forming aggregates and their role in disease.<\/jats:p>","DOI":"10.1073\/pnas.2216234120","type":"journal-article","created":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T15:15:35Z","timestamp":1684163735000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":10,"title":["Formation of amyloid loops in brain tissues is controlled by the flexibility of protofibril chains"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6980-9794","authenticated-orcid":false,"given":"Alyssa","family":"Miller","sequence":"first","affiliation":[{"name":"Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4146-0604","authenticated-orcid":false,"given":"Jiapeng","family":"Wei","sequence":"additional","affiliation":[{"name":"Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2778-4373","authenticated-orcid":false,"given":"Sarah","family":"Meehan","sequence":"additional","affiliation":[{"name":"Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Dobson","sequence":"additional","affiliation":[{"name":"Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4157-5826","authenticated-orcid":false,"given":"Mark E.","family":"Welland","sequence":"additional","affiliation":[{"name":"Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge CB3 0FF, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7116-6954","authenticated-orcid":false,"given":"David","family":"Klenerman","sequence":"additional","affiliation":[{"name":"Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3616-1610","authenticated-orcid":false,"given":"Michele","family":"Vendruscolo","sequence":"additional","affiliation":[{"name":"Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1232-1907","authenticated-orcid":false,"given":"Francesco Simone","family":"Ruggeri","sequence":"additional","affiliation":[{"name":"Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom"},{"name":"Laboratory of Organic Chemistry, Department of Agrotechnology and Food Sciences, Wageningen University &amp; Research, Wageningen 6703 WE, the Netherlands"},{"name":"Physical Chemistry, Department of Agrotechnology and Food Sciences, Wageningen University &amp; Research, Wageningen 6703 WE, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuomas P. 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Diffusible highly bioactive oligomers represent a critical minority of soluble a \u03b2 in Alzheimer\u2019s disease brain. Acta Neuropathol. 136 19\u201340 (2018).","DOI":"10.1007\/s00401-018-1846-7"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","unstructured":"D. I. Sideris et al . Soluble amyloid beta-containing aggregates are present throughout the brain at early stages of Alzheimer\u2019s disease. Brain Commun. 3 fcab147 (2021).","DOI":"10.1093\/braincomms\/fcab147"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3028"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","unstructured":"S. De et al . Different soluble aggregates of A \u03b2 42 can give rise to cellular toxicity through different mechanisms. Nat. Commun. 10 1\u201311 (2019).","DOI":"10.1038\/s41467-019-09477-3"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","unstructured":"G. M. Shankar et al . 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