Anti-amyloid antibody effects on Aβ-42 protein aggregates profiled using nanospectroscopy

Abstract Anti-amyloid beta (Aβ) drugs such as aducanumab and lecanemab are designed to clear brain amyloids and slow Alzheimer’s disease (AD) progression. While immunoassays provide ensemble-level details on anti-Aβ drug interactions with protein targets, their interfacial effects are largely unknown at a single-particle level. Here, we profile untreated and aducanumab-treated Aβ-42 protein aggregates from oligomers to fibrils using atomic force microscopy coupled with infrared spectroscopy (nanospectroscopy). Based on the recorded morphological and secondary structure details of aducanumab-treated Aβ-42 aggregates using nanospectroscopy, we observed a reduction in oligomer prevalence and formation of larger diameter fibril bundles compared to identically prepared untreated-Aβ-42 peptides. Conversely, controls based on lecanemab did not reveal any quenching of the Aβ-42 oligomer generation. Moreover, lecanemab was evidenced to bind along the full length of the Aβ-42 protofibril surface preferentially. Importantly, the structure of Aβ-42 fibrils did not disassemble in both studies upon the adsorption of aducanumab and lecanemab. Additional experiments were also conducted, such as aggregation kinetic assays and Fourier transform infrared spectroscopy on aducanumab and lecanemab-treated Aβ-42 protein aggregates that corroborated the findings from nanospectroscopy studies. Our work highlights the usefulness of nanospectroscopy in studying elemental anti-amyloid antibody interactions with protein biomarkers, a requisite for improving Alzheimer’s disease-modifying treatments. Competing Interest Statement The authors have declared no competing interest.