Aducanumab, a human IgG1 antibody with plaque-clearing effects and modest clinical benefit, binds selectively to aggregated Aβ via the N-terminal region. Yet, the molecular details of how the antibodies engage Aβ 1-42 fibrils remain unresolved. Using magic-angle spinning nuclear magnetic resonance, we show that binding of aducanumab preserves the overall architecture of the Aβ 1–42 fibril core while inducing significant structural and dynamic perturbations in the N-terminal region. Antibody binding markedly reduces flexibility in this domain with the appearance of sidechain resonances from residues D1, E3, and histidine (likely H6) in dipolar-based experiments. These sidechains—previously observed in scalar-coupling spectra of the unbound state—indicate rigidification of residues that were dynamic. The interaction extends to S8 and Y10, indicating broader fibril engagement than the minimal epitope (residues 3–7) defined in fragment-based studies. Perturbations in the C-terminal segment (G37–A42) are consistent with its spatial proximity to the antibody-bound N termini of neighboring monomers. Cryo-TEM images reveal fibrils bundling in the presence of aducanumab, consistent with lateral association via antibody cross-linking, supporting a model where surface coating and steric hindrance suppress secondary nucleation. This mode of action restricts monomer access to catalytic sites on fibril surface, resulting in partial inhibition (∼3-fold reduction) of secondary nucleation. The effect depends on high avidity and relatively high stoichiometry, but is ultimately limited by antibody size relative to N-terminal spacing along the fibril. These findings provide atomic-level insights into aducanumab’s binding mode and supply a structural framework for understanding antibody-mediated fibril recognition and for guiding next-generation therapies targeting Aβ aggregates in Alzheimer’s disease.
Palani et al. (Sun,) studied this question.