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.