Aducanumab binding to Aβ1-42 fibrils alters dynamics of the N-terminal tail while preserving the fibril core
(2025) In Proceedings of the National Academy of Sciences of the United States of America 122(52).- Abstract
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 antibody engages Aβ1-42 fibrils remain unresolved. Using magic-angle spinning NMR, we show that binding of aducanumab preserves the overall architecture of the Aβ1-42 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 side-chain resonances from residues D1, E3, and histidine (likely H6) in dipolar-based experiments. These side chains—previously observed in scalar-coupling spectra of the... (More)
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 antibody engages Aβ1-42 fibrils remain unresolved. Using magic-angle spinning NMR, we show that binding of aducanumab preserves the overall architecture of the Aβ1-42 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 side-chain resonances from residues D1, E3, and histidine (likely H6) in dipolar-based experiments. These side chains—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 to 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 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’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.
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- author
- Palani, Ravi Shankar ; Williams, Christopher G. ; Thacker, Dev LU ; Silvers, Robert ; Qian, Fang ; Weinreb, Paul H. ; Mueller, Leonard J. ; Linse, Sara LU and Griffin, Robert G.
- organization
- publishing date
- 2025-12-22
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- aducanumab, amyloid-β, antibody, magic angle spinning, magic-angle spinning
- in
- Proceedings of the National Academy of Sciences of the United States of America
- volume
- 122
- issue
- 52
- article number
- e2515673122
- publisher
- National Academy of Sciences
- external identifiers
-
- scopus:105025600815
- pmid:41428870
- ISSN
- 0027-8424
- DOI
- 10.1073/pnas.2515673122
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: Copyright © 2025 the Author(s)
- id
- 15a80a51-7361-4556-b3cb-2d2d436b26d7
- date added to LUP
- 2026-02-10 14:05:44
- date last changed
- 2026-02-11 03:00:06
@article{15a80a51-7361-4556-b3cb-2d2d436b26d7,
abstract = {{<p>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 antibody engages Aβ<sub>1-42</sub> fibrils remain unresolved. Using magic-angle spinning NMR, we show that binding of aducanumab preserves the overall architecture of the Aβ<sub>1-42</sub> 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—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 to 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 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’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.</p>}},
author = {{Palani, Ravi Shankar and Williams, Christopher G. and Thacker, Dev and Silvers, Robert and Qian, Fang and Weinreb, Paul H. and Mueller, Leonard J. and Linse, Sara and Griffin, Robert G.}},
issn = {{0027-8424}},
keywords = {{aducanumab; amyloid-β; antibody; magic angle spinning; magic-angle spinning}},
language = {{eng}},
month = {{12}},
number = {{52}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences of the United States of America}},
title = {{Aducanumab binding to Aβ<sub>1-42</sub> fibrils alters dynamics of the N-terminal tail while preserving the fibril core}},
url = {{http://dx.doi.org/10.1073/pnas.2515673122}},
doi = {{10.1073/pnas.2515673122}},
volume = {{122}},
year = {{2025}},
}