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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月28日

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

摘要

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.