Structural analysis of the asymmetric interaction between amyloid β42 and α-Synuclein: Amyloid β42 oligomers promote α-synuclein aggregation while α-synuclein inhibits amyloid β42 aggregation.

Amyloid β (Aβ) and α-synuclein (α-syn) have traditionally been recognized as the major causative proteins in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. However, AD and PD share many common pathogenic mechanisms and exhibit overlapping pathological features. Furthermore, multiple studies have reported the coexistence of Aβ and α-syn within the same pathological regions in individual patients, suggesting that such pathological coexistence is involved in disease progression and pathogenesis. However, the detailed mechanisms by which Aβ and α-syn influence each other and modulate their aggregation dynamics remain unclear. We previously established a method to observe the aggregation processes of Aβ and α-syn in two and three dimensions by utilizing the affinity between quantum dots (QDs) and amyloid aggregates, using fluorescence microscopy and confocal laser scanning microscopy. In this study, we used QD imaging, thioflavin T (ThT) fluorescence assays, and transmission electron microscopy (TEM) to evaluate in detail how Aβ42 and α-syn affect each other's aggregation behaviors. We found that 1 μM Aβ42 monomers did not affect the aggregation of 20 μM α-syn, whereas 1 μM Aβ42 oligomers significantly promoted 20 μM α-syn aggregation. In contrast, 1-10 μM α-syn inhibited the aggregation of 20 μM Aβ42 in a concentration-dependent manner, with α-syn polymers showing a stronger inhibitory effect than α-syn monomers. Taken together, these results demonstrate an asymmetry in their mutual effects on aggregation under the experimental conditions examined in this study: Aβ42 oligomers promote α-syn aggregation, whereas α-syn inhibits Aβ42 aggregation, particularly in its polymeric form.