Structural Superimposition

Abstact

Amyloid assembly in vivo occurs in complex environments where multiple aggregation-prone species coexist. Abeta 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 Abeta40 and medin. From the same reaction, we resolve three distinct fibril populations: (i) a previously characterized Abeta40 polymorph that also forms in isolation, (ii) a Abeta40 polymorph with Abeta42-like features, including ordered N- and C-terminal regions, and (iii) the atomic structure of full-length medin fibrils. Biochemical and immunogold analyses demonstrate Abeta-medin association within mixed assemblies, though medin is not resolved within the ordered Abeta core. These findings support two non-exclusive mechanisms: transient heterotypic interactions redirecting Abeta folding, or partial medin incorporation into fibril architecture. Our data reveal how coexisting amyloids remodel each other's polymorphic landscapes.