Issue 8, 2022

Amyloid-β peptide 37, 38 and 40 individually and cooperatively inhibit amyloid-β 42 aggregation

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.

Graphical abstract: Amyloid-β peptide 37, 38 and 40 individually and cooperatively inhibit amyloid-β 42 aggregation

Supplementary files

Article information

Article type
Edge Article
Submitted
02 jun 2021
Accepted
22 jan 2022
First published
07 feb 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2022,13, 2423-2439

Amyloid-β peptide 37, 38 and 40 individually and cooperatively inhibit amyloid-β 42 aggregation

G. A. Braun, A. J. Dear, K. Sanagavarapu, H. Zetterberg and S. Linse, Chem. Sci., 2022, 13, 2423 DOI: 10.1039/D1SC02990H

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