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

Abstract

Amyloid assembly in vivo occurs in complex proteomic environments where multiple aggregation-prone species coexist. A{beta} and medin are two highly prevalent amyloids in ageing humans, and medin co-localizes with A{beta} in cerebral amyloid angiopathy (CAA). Yet the structural consequences of their interaction remain unclear. Here, we determine the cryo-electron microscopy (cryo-EM) structures of fibrils formed from defined in vitro mixtures of A{beta}40 and medin. From the same reaction, we resolve three fibril populations: (i) a previously described A{beta}40 polymorph that also forms in isolation, (ii) a novel A{beta}40 polymorph with A{beta}42-like features, including ordered N- and C-terminal regions, and (iii) the first atomic structure of full-length medin fibrils. Biochemical and immunogold analyses demonstrate association between A{beta} and medin within the mixed assemblies. However, the cryo-EM map of the novel A{beta} polymorph does not unambiguously resolve medin within the ordered A{beta} core. These findings are consistent with two non-exclusive mechanisms by which the polymorphic landscape is reshaped in mixtures: transient heterotypic amyloid interactions that redirect A{beta} folding pathways, or partial and structurally heterogeneous incorporation of medin into the fibril architecture. Regardless of the precise structural mechanism, our data demonstrate that interactions between coexisting amyloids can remodel their polymorphic landscape, revealing how mixed amyloid systems generate emergent conformations.