Medin is one of a number of different amyloids that form in aging tissue, each a protein that can misfold in ways that encourage other molecules of the same protein to do the same, aggregating together to form solid deposits. Some amyloids are evidently toxic and disease-associated, while others, like medin, originally appeared more innocuous. It isn't harmless, however, just more subtle. Recent research suggested a pathological role for medin amyloid in Alzheimer's disease, in that it accelerates the aggregation of amyloid-β. Further, there is evidence for medin aggregation to contribute to cerebrovascular dysfunction. On that topic, researchers here note that cellular senescence in the vascular smooth muscle of blood vessel walls can provoke greater medin aggregation in that tissue, providing a link between those two distinct mechanisms of aging.
Vascular amyloidosis, caused when peptide monomers aggregate into insoluble amyloid, is a prevalent age-associated pathology. Aortic medial amyloid (AMA) is the most common human amyloid and is composed of medin, a 50-amino acid peptide. Emerging evidence has implicated extracellular vesicles (EVs) as mediators of pathological amyloid accumulation in the extracellular matrix (ECM). To determine the mechanisms of AMA formation with age, we explored the impact of vascular smooth muscle cell (VSMC) senescence, EV secretion, and ECM remodeling on medin accumulation.
Medin was detected in EVs secreted from primary VSMCs. Small, round medin aggregates colocalized with EV markers in decellularized ECM in vitro and medin was shown on the surface of EVs deposited in the ECM. Decreasing EV secretion with an inhibitor attenuated aggregation and deposition of medin in the ECM. Medin accumulation in the aortic wall of human subjects was strongly correlated with age and VSMC senescence increased EV secretion, increased EV medin loading, and triggered deposition of fibril-like medin.
Proteomic analysis showed VSMC senescence induced changes in EV cargo and ECM composition, which led to enhanced EV-ECM binding and accelerated medin aggregation. Abundance of the proteoglycan, HSPG2, was increased in the senescent ECM and colocalized with EVs and medin. Isolated EVs selectively bound to HSPG2 in the ECM and its knock-down decreased formation of fibril-like medin structures. These data identify VSMC-derived EVs and HSPG2 in the ECM as key mediators of medin accumulation, contributing to age-associated AMA development.