The complexity of extracellular vesicles: Bridging the gap between cellular communication and neuropathology

Brain-derived extracellular vesicles (EVs) serve a prominent role in maintaining homeostasis and contributing to pathology in health and disease. This review establishes a crucial link between physiological processes leading to EV biogenesis and their impacts on disease. EVs are involved in the clearance and transport of proteins and nucleic acids, responding to changes in cellular processes associated with neurodegeneration, including autophagic disruption, organellar dysfunction, aging, and other cell stresses. In neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, etc.), EVs contribute to the spread of pathological proteins like amyloid beta, tau, alpha-synuclein, prions, and TDP-43, exacerbating neurodegeneration and accelerating disease progression. Despite evidence for both neuropathological and neuroprotective effects of EVs, the mechanistic switch between their physiological and pathological functions remains elusive, warranting further research into their involvement in neurodegenerative disease. Moreover, owing to their innate ability to traverse the blood-brain barrier and their ubiquitous nature, EVs emerge as promising candidates for novel diagnostic and therapeutic strategies. The review uniquely positions itself at the intersection of EV cell biology, neurophysiology, and neuropathology, offering insights into the diverse biological roles of EVs in health and disease. Extracellular vesicles are ubiquitous to all cells, but their role in biology and pathology is multifaceted. In this report, we review the roles that extracellular vesicles can play in biological processes and cellular dysfunction and pathobiology, particularly neurodegenerative diseases. We also examine the potential translational impacts of extracellular vesicles in diagnostics and therapeutic development. ER: endoplasmic reticulum; ROS: reactive oxygen species.image