Critical aggregation concentration and reversibility of amyloid-β (1–40) oligomers

Abstract

Amyloid-beta (Aβ) aggregation is a critical factor in the pathogenesis of Alzheimer's disease, with distinct aggregation behaviours observed between its isoforms Amyloid-β 1–40 (Aβ40) and 1–42 (Aβ42). In this study, we investigated the aggregation properties of Aβ40 using fluorescence correlation spectroscopy (FCS) and detailed data analysis. Our results reveal that Aβ40 undergoes a two-step cooperative aggregation process. The first step, characterized by a critical aggregation concentration (cac) of 0.5 ± 0.3 μM, results in the formation of metastable oligomers of 5–25 monomers and stable oligomers of 50–100 monomers, with less than 10 % of the total amyloid aggregated. The second step, with a cac of 19 ± 2 μM, leads to the formation of much larger aggregates, consistent with protofibrils, and approximately 50 % aggregated amyloid. Notably, the cac for Aβ40 is significantly higher, and the fraction of aggregated amyloid is much lower compared to Aβ42, indicating a lower propensity for aggregation. Additionally, our findings suggest that Aβ40 early oligomers are reversible upon dilution, albeit with a kinetic barrier to disaggregation. These insights into the aggregation mechanisms of Aβ40 enhance our understanding of its role in Alzheimer's disease and may inform therapeutic strategies targeting amyloid aggregation