Journal Article

DZNE-2026-00705

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Atomic structures of medin and Aβ fibrils reveal polymorphic remodeling in mixed amyloid systems.

Pradhan, B. ; Kumar, S. T. ; Wagner, J.DZNE* ; Gallardo, R. ; Orlando, G. ; De Vleeschouwer, M. ; Zorzini, V. ; Madine, J. ; Louros, N. ; Neher, J. J.DZNE* ; Rousseau, F. ; Schymkowitz, J.

2026
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-026-72515-4

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.

Keyword(s): Amyloid beta-Peptides: chemistry (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Amyloid beta-Peptides: ultrastructure (MeSH) ; Cryoelectron Microscopy (MeSH) ; Amyloid: chemistry (MeSH) ; Amyloid: ultrastructure (MeSH) ; Amyloid: metabolism (MeSH) ; Humans (MeSH) ; Peptide Fragments: chemistry (MeSH) ; Peptide Fragments: metabolism (MeSH) ; Peptide Fragments: ultrastructure (MeSH) ; Tenascin: chemistry (MeSH) ; Tenascin: metabolism (MeSH) ; Tenascin: ultrastructure (MeSH) ; Antigens, Surface (MeSH) ; Milk Proteins (MeSH) ; Amyloid beta-Peptides ; Amyloid ; Peptide Fragments ; MFGE8 protein, human ; Tenascin ; amyloid beta-protein (1-40) ; Antigens, Surface ; Milk Proteins

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Contributing Institute(s):

1. Neuroimmunology and Neurodegenerative Disease (AG Neher (München))

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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