Extracellular vesicles and their synthetic analogues in aging and age-associated brain diseases

Abstract

Multicellular organisms rely upon diverse and complex intercellular communications networks for a myriad of physiological processes. Disruption of these processes is implicated in the onset and propagation of disease and disorder, including the mechanisms of senescence at both cellular and organismal levels. In recent years, secreted extracellular vesicles (EVs) have been identified as a particularly novel vector by which cell-to-cell communications are enacted. EVs actively and specifically traffic bioactive proteins, nucleic acids, and metabolites between cells at local and systemic levels, modulating cellular responses in a bidirectional manner under both homeostatic and pathological conditions. EVs are being implicated not only in the generic aging process, but also as vehicles of pathology in a number of age-related diseases, including cancer and neurodegenerative and disease. Thus, circulating EVs-or specific EV cargoes-are being utilised as putative biomarkers of disease. On the other hand, EVs, as targeted intercellular shuttles of multipotent bioactive payloads, have demonstrated promising therapeutic properties, which can potentially be modulated and enhanced through cellular engineering. Furthermore, there is considerable interest in employing nanomedicinal approaches to mimic the putative therapeutic properties of EVs by employing synthetic analogues for targeted drug delivery. Herein we describe what is known about the origin and nature of EVs and subsequently review their putative roles in biology and medicine (including the use of synthetic EV analogues), with a particular focus on their role in aging and age-related brain diseases.

Fig. 1

The four general pathways of membrane vesicle biogenesis. 1 Exosomes arise from an endocytic pathway that begins with the invagination of receptor-coated plasma membrane to form an endosome (endocytic receptors are depicted in purple). 2 Intraluminal vesicles bud off into the endosome, passively or actively incorporating bioactive molecules as they do so. 3 The endosome matures into a MVB, which is subsequently destined for either degradation within a lysosome, or 4 exocytosis whereby exosomal EVs are released into the extracellular milieu. 5 Microvesicles (shedding vesicles) arise from direct budding and fission of portions of the plasma membrane, encapsulating a cargo of cytoplasmic proteins (depicted in yellow) and nucleic acids from the cytosol as they do so. Variables such as the nature or pathological state of the parent cell will influence the type and contents of EVs. 6 The shrinkage and fragmentation of apoptotic cells gives rise to so-called apoptotic bodies or blebs, 7 while an unknown mechanism believed to involve transcription of endogenous retroviruses leads to the formation of RLPs. (Color figure online)

Fig. 2

Types of synthetic EV analogue nanovehicles. Liposomes (a) are membrane bilayers enclosing an aqueous/hydrophilic interior. Polymersomes (b) are comprised of amphiphilic block copolymers that self-assemble into a sphere with a hydrophobic layer sandwiched between a hydrophilic core and surface. Micelles (c) also consist of amphiphilic block copolymers, but assembled into a sphere with a hydrophobic core and hydrophilic exterior. Polyplexes (d), like their lipid or protein-based analogues, complex polyanionic nucleic acids via electrostatic interactions with cationic polymers. Dendrimers (e) are unimolecular, branched spherical assemblies with dense, hydrophobic surfaces but relatively empty pockets nearer the core in which to encapsulate drugs. (Color figure online)