Atomic structures of medin and Aβ fibrils reveal polymorphic remodeling in mixed amyloid systems

Amyloid assembly in vivo occurs in complex environments where multiple aggregation-prone species coexist. Aβ and medin are prevalent amyloids in ageing humans that co-localize in cerebral amyloid angiopathy (CAA), yet their structural interactions remain poorly understood. Here, using cryo-electron microscopy, we determine high-resolution fibril structures from in vitro mixtures of Aβ40 and medin. From the same reaction, we resolve three distinct fibril populations: (i) a previously characterized Aβ40 polymorph that also forms in isolation, (ii) a Aβ40 polymorph with Aβ42-like features, including ordered N- and C-terminal regions, and (iii) the atomic structure of full-length medin fibrils. Biochemical and immunogold analyses demonstrate Aβ-medin association within mixed assemblies, though medin is not resolved within the ordered Aβ core. These findings support two non-exclusive mechanisms: transient heterotypic interactions redirecting Aβ folding, or partial medin incorporation into fibril architecture. Our data reveal how coexisting amyloids remodel each other's polymorphic landscapes.

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Publication Details

Journal
Nature Communications
Published
2026-04-28
DOI
https://doi.org/10.1038/s41467-026-72515-4
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
0.00

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article

Atomic structures of medin and Aβ fibrils reveal polymorphic remodeling in mixed amyloid systems

Frédéric Rousseau, Joost Schymkowitz, Jonas J. Neher, Nikolaos Louros et al.
Nature Communications
Alzheimer's disease research and treatments
article

Atomic structures of medin and Aβ fibrils reveal polymorphic remodeling in mixed amyloid systems

Frédéric Rousseau, Joost Schymkowitz, Jonas J. Neher, Nikolaos Louros, Brajabandhu Pradhan, Matthias De Vleeschouwer, Gabriele Orlando, Jillian Madine, Senthil T. Kumar, Rodrigo Gallardo, Jessica Wagner, Valentina Zorzini
article en

Abstract

Amyloid assembly in vivo occurs in complex environments where multiple aggregation-prone species coexist. Aβ and medin are prevalent amyloids in ageing humans that co-localize in cerebral amyloid angiopathy (CAA), yet their structural interactions remain poorly understood. Here, using cryo-electron microscopy, we determine high-resolution fibril structures from in vitro mixtures of Aβ40 and medin. From the same reaction, we resolve three distinct fibril populations: (i) a previously characterized Aβ40 polymorph that also forms in isolation, (ii) a Aβ40 polymorph with Aβ42-like features, including ordered N- and C-terminal regions, and (iii) the atomic structure of full-length medin fibrils. Biochemical and immunogold analyses demonstrate Aβ-medin association within mixed assemblies, though medin is not resolved within the ordered Aβ core. These findings support two non-exclusive mechanisms: transient heterotypic interactions redirecting Aβ folding, or partial medin incorporation into fibril architecture. Our data reveal how coexisting amyloids remodel each other's polymorphic landscapes.

Nature Communications
Centre National de la Recherche Scientifique (FR), University of Liverpool (GB), Inserm (FR), Université de Montpellier (FR), German Center for Neurodegenerative Diseases (DE), VIB-KU Leuven Center for Cancer Biology (BE), Southwestern Medical Center (US), National Centre for Cell Science (IN), Munich Cluster for Systems Neurology (DE), VIB-KU Leuven Center for Microbiology (BE), Hertie Institute for Clinical Brain Research (DE), VIB-KU Leuven Center for Brain & Disease Research (BE), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), The University of Texas Southwestern Medical Center (US), KU Leuven (BE)
Diamond Light Source, University of Leeds, Fonds Wetenschappelijk Onderzoek, Ludwig-Maximilians-Universität München, Vlaamse regering, National Institutes of Health
Openalex Percentile: Top 10%
Alzheimer's disease research and treatments
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