Journal Article

FZJ-2025-04506

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Anle138b binds predominantly to the central cavity in lipidic Aβ₄₀ fibrils and modulates fibril formation

Han, M. ; Frieg, B. ; Matthes, D. ; Leonov, A. ; Ryazanov, S. ; Giller, K. ; Nimerovsky, E. ; Stampolaki, M. ; Xue, K. ; Overkamp, K. ; Dienemann, C. ; Riedel, D. ; Giese, A. ; Becker, S. ; de Groot, B. L. ; Schröder, G. F.FZJ* ; Andreas, L. B. (Corresponding author) ; Griesinger, C. (Corresponding author)

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-64443-6  doi:10.34734/FZJ-2025-04506

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 andmay inform the development of therapies and diagnostic approaches. In addition, anle138b reduces fibril formation in the presence of lipids by approximately 75%. Thismay suggest amechanistic connection to its previously reported activity in animal models of Alzheimer’s disease.

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Contributing Institute(s):

1. Strukturbiochemie (IBI-7)

Research Program(s):

1. 5244 - Information Processing in Neuronal Networks (POF4-524) (POF4-524)

Appears in the scientific report 2025

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