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