Anle138b binds predominantly to the central cavity in lipidic Aβ₄₀ fibrils and modulates fibril formation

Mookyoung Han, Benedikt Frieg, Dirk Matthes, Andrei Leonov, Sergey Ryazanov, Karin Giller, Evgeny Nimerovsky, Marianna Stampolaki, Kai Xue, Kerstin Overkamp, Christian Dienemann, Dietmar Riedel, Armin Giese, Stefan Becker, Bert L. Groot, Gunnar F. Schröder, Loren B. Andreas () and Christian Griesinger ()
Additional contact information
Mookyoung Han: Max Planck Institute for Multidisciplinary Sciences
Benedikt Frieg: Forschungszentrum Jülich
Dirk Matthes: Max Planck Institute for Multidisciplinary Sciences
Andrei Leonov: Max Planck Institute for Multidisciplinary Sciences
Sergey Ryazanov: Max Planck Institute for Multidisciplinary Sciences
Karin Giller: Max Planck Institute for Multidisciplinary Sciences
Evgeny Nimerovsky: Max Planck Institute for Multidisciplinary Sciences
Marianna Stampolaki: Max Planck Institute for Multidisciplinary Sciences
Kai Xue: Max Planck Institute for Multidisciplinary Sciences
Kerstin Overkamp: Max Planck Institute for Multidisciplinary Sciences
Christian Dienemann: Max Planck Institute for Multidisciplinary Sciences
Dietmar Riedel: Max-Planck-Institute for Multidisciplinary Sciences
Armin Giese: Mikroforum Ring 3
Stefan Becker: Max Planck Institute for Multidisciplinary Sciences
Bert L. Groot: Max Planck Institute for Multidisciplinary Sciences
Gunnar F. Schröder: Forschungszentrum Jülich
Loren B. Andreas: Max Planck Institute for Multidisciplinary Sciences
Christian Griesinger: Max Planck Institute for Multidisciplinary Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Alzheimer’s disease is a specific neurodegenerative disorder, distinct from normal aging, with a growing unmet medical need. It is characterized by the accumulation of amyloid plaques in the brain, primarily consisting of amyloid beta (Aβ) fibrils. Therapeutic antibodies can slow down the disease, but are associated with potential severe side effects, motivating the development of small molecules to halt disease progression. This study investigates the interaction between the clinical drug candidate small molecule anle138b and lipidic Aβ₄₀ fibrils of type 1 (L1). L1 fibrils were previously shown to closely resemble fibrils from Alzheimer’s patients. Using high-resolution structural biology techniques, including cryo-electron microscopy (cryo-EM), nuclear magnetic resonance (NMR) spectroscopy enhanced by dynamic nuclear polarization (DNP), and molecular dynamics (MD) simulations, we find that anle138b selectively binds to a cavity within the fibril. This structural insight provides a deeper understanding of a potential drug-binding mechanism at the atomic level and may inform the development of therapies and diagnostic approaches. In addition, anle138b reduces fibril formation in the presence of lipids by approximately 75%. This may suggest a mechanistic connection to its previously reported activity in animal models of Alzheimer’s disease.

Date: 2025
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DOI: 10.1038/s41467-025-64443-6

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