The secret life of extracellular vesicles in metal homeostasis and neurodegeneration

Biologically active metals such as copper, zinc and iron are fundamental for sustaining life in different organisms with the regulation of cellular metal homeostasis tightly controlled through proteins that coordinate metal uptake, efflux and detoxification. Many of the proteins involved in either uptake or efflux of metals are localised and function on the plasma membrane, traffic between intracellular compartments depending upon the cellular metal environment and can undergo recycling via the endosomal pathway. The biogenesis of exosomes also occurs within the endosomal system, with several major neurodegenerative disease proteins shown to be released in association with these vesicles, including the amyloid‐β (Aβ) peptide in Alzheimer's disease and the infectious prion protein involved in Prion diseases. Aβ peptide and the prion protein also bind biologically active metals and are postulated to play important roles in metal homeostasis. In this review, we will discuss the role of extracellular vesicles in Alzheimer's and Prion diseases and explore their potential contribution to metal homeostasis. Review The intercellular spread and secretion of neurodegenerative disease associated proteins amyloid precursor protein (APP), Amyloid‐β (Aβ) and the Prion protein (PrP) in extracellular vesicles, such as exosomes, is an emerging field of research. Cellular metal levels are tightly regulated by the actions of proteins involved in uptake, detoxification or secretion. APP, Aβ and PrP also contain binding sites for copper, zinc and iron and may function in metal homeostasis via exosomal release.