In the ageing brain, amyloid proteins rarely act alone. Amyloid-β (Aβ), the hallmark of Alzheimer's disease, and medin, the most prevalent amyloid in humans over 50, frequently co-deposit in the walls of cerebral blood vessels. But how do two aggregating proteins influence each other's structure when they meet? Until now, we have lacked an atomic-resolution answer.
\nUsing cryo-electron microscopy on in vitro mixtures of Aβ40 and medin, we resolved three coexisting fibril populations from a single reaction. The first is a familiar Aβ40 polymorph also seen in pure samples. The second is striking: an Aβ40 fibril with ordered N- and C-terminal regions that structurally resembles Aβ42, a fold that does not appear when Aβ40 aggregates alone. The third is the first atomic structure of full-length medin, revealing an unusual \"r\"-shaped fold stabilised by a rare polar steric zipper.
\nBiochemical and immunogold experiments confirm that medin and Aβ associate within mixed assemblies, even though medin is not rigidly built into the Aβ core. Together, the results show that heterotypic amyloid interactions need not produce a single hybrid fibril; instead, they can expand and reshape the polymorphic landscape, offering a structural framework for understanding amyloid strain selection in ageing-associated vascular pathology.
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