Computational insights into the cross-talk between medin and Aβ: implications for age-related vascular risk factors in Alzheimer's disease

Abstract

The aggregation of medin forming aortic medial amyloid is linked to arterial wall degeneration and cerebrovascular dysfunction. Elevated levels of arteriolar medin are correlated with an increased presence of vascular amyloid-β (Aβ) aggregates, a hallmark of Alzheimer's disease (AD) and vascular dementia. The cross-interaction between medin and Aβ results in the formation of heterologous fibrils through co-aggregation and cross-seeding processes both in vitro and in vivo. However, a comprehensive molecular understanding of the cross-interaction between medin and Aβ-two intrinsically disordered proteins-is critically lacking. Here, we employed atomistic discrete molecular dynamics simulations to systematically investigate the self-association, co-aggregation and also the phenomenon of cross-seeding between these two proteins. Our results demonstrated that both Aβ and medin were aggregation prone and their mixture tended to form β-sheet-rich hetero-aggregates. The formation of Aβ-medin hetero-aggregates did not hinder Aβ and medin from recruiting additional Aβ and medin peptides to grow into larger β-sheet-rich aggregates. The β-barrel oligomer intermediates observed in the self-aggregations of Aβ and medin were also present during their co-aggregation. In cross-seeding simulations, preformed Aβ fibrils could recruit isolated medin monomers to form elongated β-sheets. Overall, our comprehensive simulations suggested that the cross-interaction between Aβ and medin may contribute to their pathological aggregation, given the inherent amyloidogenic tendencies of both medin and Aβ. Targeting medin, therefore, could offer a novel therapeutic approach to preserving brain function during aging and AD by improving vascular health.

Keywords: amyloid aggregation; amyloid-β; co-aggregation; cross-seeding; discrete molecular dynamics; medin.