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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,12,30]]},"abstract":"<jats:p>\n                    Aducanumab, a human IgG1 antibody with plaque-clearing effects and modest clinical benefit, binds selectively to aggregated A\u03b2 via the N-terminal region. Yet, the molecular details of how the antibody engages A\u03b2\n                    <jats:sub>1-42<\/jats:sub>\n                    fibrils remain unresolved. Using magic-angle spinning NMR, we show that binding of aducanumab preserves the overall architecture of the A\u03b2\n                    <jats:sub>1-42<\/jats:sub>\n                    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 side-chain resonances from residues D1, E3, and histidine (likely H6) in dipolar-based experiments. These side chains\u2014previously observed in scalar-coupling spectra of the unbound state\u2014indicate rigidification of residues that were dynamic. The interaction extends to S8 and Y10, indicating broader fibril engagement than the minimal epitope (residues 3 to 7) defined in fragment-based studies. Perturbations in the C-terminal segment (G37\u2013A42) 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 the fibril surface, resulting in partial inhibition (~threefold 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\u2019s binding mode and supply a structural framework for understanding antibody-mediated fibril recognition and for guiding next-generation therapies targeting A\u03b2 aggregates in Alzheimer\u2019s disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2515673122","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T20:00:56Z","timestamp":1766433656000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["Aducanumab binding to A\u03b2\n                    <sub>1-42<\/sub>\n                    fibrils alters dynamics of the N-terminal tail while preserving the fibril core"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3528-7788","authenticated-orcid":false,"given":"Ravi Shankar","family":"Palani","sequence":"first","affiliation":[{"name":"Department of Chemistry and Francis Bitter 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