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

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, Aβ 37 and Aβ 38 , as pure peptides and in mixtures with Aβ 40 and Aβ 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 Aβ 42 . Through kinetic analysis, we show that both Aβ 37 and Aβ 38 self-assemble through an autocatalytic secondary nucleation reaction to form fibrillar β-sheet-rich aggregates, albeit on a longer timescale than Aβ 40 or Aβ 42 . Additionally, we show that the shorter alloforms co-aggregate with Aβ 40 , affecting both the kinetics of aggregation and the resulting fibrillar ultrastructure. In contrast, neither Aβ 37 nor Aβ 38 forms co-aggregates with Aβ 42 ; however, both short alloforms reduce the rate of Aβ 42 aggregation in a concentration-dependent manner. Finally, we show that the aggregation of Aβ 42 is more significantly impeded by a combination of Aβ 37 , Aβ 38 , and Aβ 40 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.