TY  - JOUR
EP  - 2439
SP  - 2423
N2  - The pathology of Alzheimer's disease is connected to the aggregation of ?-amyloid (A?) 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, A?37 and A?38, as pure peptides and in mixtures with A?40 and A?42. A variety of molar ratios were applied in quaternary mixtures to investigate whether a certain ratio is maximally inhibiting of the more toxic alloform A?42. Through kinetic analysis, we show that both A?37 and A?38 self-assemble through an autocatalytic secondary nucleation reaction to form fibrillar ?-sheet-rich aggregates, albeit on a longer timescale than A?40 or A?42. Additionally, we show that the shorter alloforms co-aggregate with A?40, affecting both the kinetics of aggregation and the resulting fibrillar ultrastructure. In contrast, neither A?37 nor A?38 forms co-aggregates with A?42; however, both short alloforms reduce the rate of A?42 aggregation in a concentration-dependent manner. Finally, we show that the aggregation of A?42 is more significantly impeded by a combination of A?37, A?38, and A?40 than by any of these alloforms independently. These results demonstrate that the aggregation of any given A? 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
A1  - Braun, Gabriel A
A1  - Dear, Alexander J
A1  - Sanagavarapu, Kalyani
A1  - Zetterberg, Henrik
A1  - Linse, Sara
AV  - public
IS  - 8
N1  - © 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/).
TI  - Amyloid-? peptide 37, 38 and 40 individually and cooperatively inhibit amyloid-? 42 aggregation
Y1  - 2022/02/28/
UR  - https://doi.org/10.1039/D1SC02990H
ID  - discovery10145146
PB  - ROYAL SOC CHEMISTRY
VL  - 13
JF  - Chemical Science
ER  -