Clusterin inhibits Aβ₄₂ aggregation through a "strawberry model" as detected by FRET-FCS

Extracellular plaque deposits of β-amyloid peptide (Aβ) are one of the main pathological features of Alzheimer's disease (AD). The aggregation of Aβ₄₂ species, especially Aβ₄₂ oligomers, is still an active research field in AD pathogenesis. Secretory clusterin protein (sCLU), an extracellular chaperone, plays an important role in AD pathogenesis. Although sCLU interacts directly with Aβ₄₂ in vitro and in vivo, the mechanism is not clear. In this paper, His-tagged sCLU (sCLU-His) was cloned, expressed and purified, and we applied florescence resonance energy transfer-fluorescence correlation spectroscopy (FRET-FCS) to investigate the direct interaction of sCLU-His and Aβ₄₂ at the single-molecule fluorescence level in vitro. Here, we chose four different fluorescently labeled Aβ₄₂ oligomers to form two different groups of aggregation models, easy or difficult to aggregate. The results showed that sCLU-His could form complexes with both aggregation models, and sCLU-His inhibited the aggregation of Aβ_42/RB  ~ Aβ_42/Atto647 (easy to aggregate model). The complexes were produced as the Aβ_42/Label adhered to the sCLU-His, which is similar to a "strawberry model," as strawberry seeds are dotted on the outer surface of strawberries. This work provided additional insight into the interaction mechanism of sCLU and Aβ₄₂ .