{"department":[{"_id":"AnSa"}],"abstract":[{"text":"Amyloid formation is linked to devastating neurodegenerative diseases, motivating detailed studies of the mechanisms of amyloid formation. For Aβ, the peptide associated with Alzheimer’s disease, the mechanism and rate of aggregation have been established for a range of variants and conditions <jats:italic>in vitro</jats:italic> and in bodily fluids. A key outstanding question is how the relative stabilities of monomers, fibrils and intermediates affect each step in the fibril formation process. By monitoring the kinetics of aggregation of Aβ42, in the presence of urea or guanidinium hydrochloride (GuHCl), we here determine the rates of the underlying microscopic steps and establish the importance of changes in relative stability induced by the presence of denaturant for each individual step. Denaturants shift the equilibrium towards the unfolded state of each species. We find that a non-ionic denaturant, urea, reduces the overall aggregation rate, and that the effect on nucleation is stronger than the effect on elongation. Urea reduces the rate of secondary nucleation by decreasing the coverage of fibril surfaces and the rate of nucleus formation. It also reduces the rate of primary nucleation, increasing its reaction order. The ionic denaturant, GuHCl, accelerates the aggregation at low denaturant concentrations and decelerates the aggregation at high denaturant concentrations. Below approximately 0.25 M GuHCl, the screening of repulsive electrostatic interactions between peptides by the charged denaturant dominates, leading to an increased aggregation rate. At higher GuHCl concentrations, the electrostatic repulsion is completely screened, and the denaturing effect dominates. The results illustrate how the differential effects of denaturants on stability of monomer, oligomer and fibril translate to differential effects on microscopic steps, with the rate of nucleation being most strongly reduced.","lang":"eng"}],"date_published":"2022-09-20T00:00:00Z","publication_status":"published","article_processing_charge":"No","month":"09","tmp":{"image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"date_updated":"2023-08-04T09:48:56Z","file":[{"date_updated":"2023-01-30T09:15:13Z","file_id":"12442","success":1,"date_created":"2023-01-30T09:15:13Z","file_size":19798610,"relation":"main_file","checksum":"e67d16113ffb4fb4fa38a183d169f210","content_type":"application/pdf","file_name":"2022_FrontiersNeuroscience_Weiffert2.pdf","access_level":"open_access","creator":"dernst"}],"type":"journal_article","day":"20","title":"Influence of denaturants on amyloid β42 aggregation kinetics","quality_controlled":"1","status":"public","publisher":"Frontiers Media","scopus_import":"1","oa":1,"oa_version":"Published Version","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","date_created":"2023-01-16T09:56:43Z","language":[{"iso":"eng"}],"_id":"12251","article_number":"943355","citation":{"chicago":"Weiffert, Tanja, Georg Meisl, Samo Curk, Risto Cukalevski, Anđela Šarić, Tuomas P. J. Knowles, and Sara Linse. “Influence of Denaturants on Amyloid Β42 Aggregation Kinetics.” <i>Frontiers in Neuroscience</i>. Frontiers Media, 2022. <a href=\"https://doi.org/10.3389/fnins.2022.943355\">https://doi.org/10.3389/fnins.2022.943355</a>.","apa":"Weiffert, T., Meisl, G., Curk, S., Cukalevski, R., Šarić, A., Knowles, T. P. J., &#38; Linse, S. (2022). Influence of denaturants on amyloid β42 aggregation kinetics. <i>Frontiers in Neuroscience</i>. Frontiers Media. <a href=\"https://doi.org/10.3389/fnins.2022.943355\">https://doi.org/10.3389/fnins.2022.943355</a>","ista":"Weiffert T, Meisl G, Curk S, Cukalevski R, Šarić A, Knowles TPJ, Linse S. 2022. Influence of denaturants on amyloid β42 aggregation kinetics. Frontiers in Neuroscience. 16, 943355.","ama":"Weiffert T, Meisl G, Curk S, et al. Influence of denaturants on amyloid β42 aggregation kinetics. <i>Frontiers in Neuroscience</i>. 2022;16. doi:<a href=\"https://doi.org/10.3389/fnins.2022.943355\">10.3389/fnins.2022.943355</a>","short":"T. Weiffert, G. Meisl, S. Curk, R. Cukalevski, A. Šarić, T.P.J. Knowles, S. Linse, Frontiers in Neuroscience 16 (2022).","mla":"Weiffert, Tanja, et al. “Influence of Denaturants on Amyloid Β42 Aggregation Kinetics.” <i>Frontiers in Neuroscience</i>, vol. 16, 943355, Frontiers Media, 2022, doi:<a href=\"https://doi.org/10.3389/fnins.2022.943355\">10.3389/fnins.2022.943355</a>.","ieee":"T. Weiffert <i>et al.</i>, “Influence of denaturants on amyloid β42 aggregation kinetics,” <i>Frontiers in Neuroscience</i>, vol. 16. Frontiers Media, 2022."},"article_type":"original","external_id":{"isi":["000866287100001"]},"publication_identifier":{"issn":["1662-453X"]},"doi":"10.3389/fnins.2022.943355","has_accepted_license":"1","author":[{"full_name":"Weiffert, Tanja","last_name":"Weiffert","first_name":"Tanja"},{"full_name":"Meisl, Georg","first_name":"Georg","last_name":"Meisl"},{"last_name":"Curk","first_name":"Samo","full_name":"Curk, Samo"},{"full_name":"Cukalevski, Risto","first_name":"Risto","last_name":"Cukalevski"},{"orcid":"0000-0002-7854-2139","id":"bf63d406-f056-11eb-b41d-f263a6566d8b","full_name":"Šarić, Anđela","first_name":"Anđela","last_name":"Šarić"},{"last_name":"Knowles","first_name":"Tuomas P. J.","full_name":"Knowles, Tuomas P. J."},{"full_name":"Linse, Sara","first_name":"Sara","last_name":"Linse"}],"publication":"Frontiers in Neuroscience","ddc":["570"],"file_date_updated":"2023-01-30T09:15:13Z","acknowledgement":"This work was supported by grants from the Swedish Research Council (grant no. 2015-00143) and the European Research Council (grant no. 340890).","isi":1,"keyword":["General Neuroscience"],"year":"2022","intvolume":"        16","volume":16}