Anle138b binds predominantly to the central cavity in lipidic Aβ₄₀ fibrils and modulates fibril formation
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.
Authors
- Karin Giller (ORCID: https://orcid.org/0000-0002-4149-7899)
- Loren B. Andreas (ORCID: https://orcid.org/0000-0003-3216-9065)
- Sergey Ryazanov (ORCID: https://orcid.org/0000-0002-2685-7956)
- Gunnar F. Schröder (ORCID: https://orcid.org/0000-0003-1803-5431)
- Evgeny Nimerovsky (ORCID: https://orcid.org/0000-0003-3002-0718)
- Μarianna Stampolaki (ORCID: https://orcid.org/0000-0002-0144-4792)
- Kerstin Overkamp
- Christian Griesinger (ORCID: https://orcid.org/0000-0002-1266-4344)
- Bert L. de Groot (ORCID: https://orcid.org/0000-0003-3570-3534)
- Stefan Becker (ORCID: https://orcid.org/0000-0003-2041-5740)
- Benedikt Frieg (ORCID: https://orcid.org/0000-0002-7877-0262)
- Dietmar Riedel (ORCID: https://orcid.org/0000-0003-2970-6894)
- Kai Xue
- Dirk Matthes (ORCID: https://orcid.org/0000-0003-3969-6335)
- Christian Dienemann (ORCID: https://orcid.org/0000-0002-2172-5110)
- Mookyoung Han (ORCID: https://orcid.org/0009-0004-8007-5711)
- Andrei Leonov (ORCID: https://orcid.org/0000-0002-5586-9382)
- Armin Giese
Institutions
- General Motors (Germany) (DE)
- Ernst Ruska Centre (DE)
- Max Planck Institute for the Study of Religious and Ethnic Diversity (DE)
- Nanoscale Microscopy and Molecular Physiology of the Brain Cluster of Excellence 171 — DFG Research Center 103 (DE)
- Max Planck Institute for Multidisciplinary Sciences (DE)
- Heinrich Heine University Düsseldorf (DE)
- University of Göttingen (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-03
- DOI
- https://doi.org/10.1038/s41467-025-64443-6
- Citations
- 1
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.16
Funders
- Deutsche Forschungsgemeinschaft
- Forschungszentrum Jülich
- Heinrich-Heine-Universität Düsseldorf
- Max-Planck-Gesellschaft