eprintid: 10145146 rev_number: 7 eprint_status: archive userid: 699 dir: disk0/10/14/51/46 datestamp: 2022-03-15 12:10:33 lastmod: 2022-03-15 12:10:33 status_changed: 2022-03-15 12:10:33 type: article metadata_visibility: show sword_depositor: 699 creators_name: Braun, Gabriel A creators_name: Dear, Alexander J creators_name: Sanagavarapu, Kalyani creators_name: Zetterberg, Henrik creators_name: Linse, Sara title: Amyloid-β peptide 37, 38 and 40 individually and cooperatively inhibit amyloid-β 42 aggregation ispublished: pub divisions: C07 divisions: F86 divisions: B02 divisions: UCL divisions: D07 note: © Royal Society of Chemistry 2022. Original content in this article is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). abstract: The pathology of Alzheimer's disease is connected to the aggregation of β-amyloid (Aβ) peptide, which in vivo exists as a number of length-variants. Truncations and extensions are found at both the N- and C-termini, relative to the most commonly studied 40- and 42-residue alloforms. Here, we investigate the aggregation of two physiologically abundant alloforms, Aβ37 and Aβ38, as pure peptides and in mixtures with Aβ40 and Aβ42. A variety of molar ratios were applied in quaternary mixtures to investigate whether a certain ratio is maximally inhibiting of the more toxic alloform Aβ42. Through kinetic analysis, we show that both Aβ37 and Aβ38 self-assemble through an autocatalytic secondary nucleation reaction to form fibrillar β-sheet-rich aggregates, albeit on a longer timescale than Aβ40 or Aβ42. Additionally, we show that the shorter alloforms co-aggregate with Aβ40, affecting both the kinetics of aggregation and the resulting fibrillar ultrastructure. In contrast, neither Aβ37 nor Aβ38 forms co-aggregates with Aβ42; however, both short alloforms reduce the rate of Aβ42 aggregation in a concentration-dependent manner. Finally, we show that the aggregation of Aβ42 is more significantly impeded by a combination of Aβ37, Aβ38, and Aβ40 than by any of these alloforms independently. These results demonstrate that the aggregation of any given Aβ alloform is significantly perturbed by the presence of other alloforms, particularly in heterogeneous mixtures, such as is found in the extracellular fluid of the brain. This journal is date: 2022-02-28 date_type: published publisher: ROYAL SOC CHEMISTRY official_url: https://doi.org/10.1039/D1SC02990H oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1943088 doi: 10.1039/d1sc02990h lyricists_name: Zetterberg, Henrik lyricists_id: HZETT94 actors_name: Kalinowski, Damian actors_id: DKALI47 actors_role: owner funding_acknowledgements: 2015-00143 [Swedish Research Council]; 2018-02532 [Swedish Research Council]; 681712 [European Research Council]; ALFGBG-720931 [Swedish State Support for Clinical Research]; [Lindemann Trust Fellowship]; NNF19OC0054635 [Novo Nordisk Foundation]; [Fulbright U.S. Student Program] full_text_status: public publication: Chemical Science volume: 13 number: 8 pagerange: 2423-2439 pages: 17 citation: Braun, Gabriel A; Dear, Alexander J; Sanagavarapu, Kalyani; Zetterberg, Henrik; Linse, Sara; (2022) Amyloid-β peptide 37, 38 and 40 individually and cooperatively inhibit amyloid-β 42 aggregation. Chemical Science , 13 (8) pp. 2423-2439. 10.1039/d1sc02990h <https://doi.org/10.1039/d1sc02990h>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10145146/1/Zetterberg_Amyloid-beta%20peptide%2037%2C%2038%20and%2040%20individually%20and%20cooperatively%20inhibit%20amyloid-beta%2042%20aggregation_VoR.pdf