‘Treasure’ in garbage bags: extracellular vesicles based biomarker for neurological diseases

Abstract

Extracellular vesicles (EVs) are microto nano-sized membrane-bound vesicles that are secreted by all cell types except viruses as part of their normal physiological function to maintain cellular homeostasis. Initially, EVs were considered as ‘garbage bags’ that cells utilize to throw their metabolic waste out. However, these vesicles were later recognized to play a crucial role in intercellular communication by transferring various biomolecules (loaded as cargos) such as proteins, nucleic acids (mostly non-coding RNAs), lipids and metabolites. Majorly EVs are divided into three subclasses: apoptotic bodies, microvesicles (MVs), and exosomes. Apoptotic bodies are released from the cells undergoing programmed cell death and range from ~50 to 5 μm in size (1,2). MVs are ~100 to ≥1,000 nm in size and arise by outward budding of the plasma membrane (3). Exosomes are derived from the endosomal system and released to the extracellular environment as ~30–150 nm size vesicles. EVs isolated from in vivo system cannot be distinguished if they are generated from the endosomal pathway or released from the outward budding of the plasma membrane. Also, due to their overlapping size and lack of specific biomarkers, it is difficult to discriminate these vesicles and, therefore, collectively referred as EVs. In the last decade, small EVs (sEVs), mainly enriched in exosomes, have garnered much attention for their role as biomarkers for several diseases, including cancer (4,5), cardiovascular disease (6,7), diabetes, and obesity (8,9), inflammation (10) and psychiatric disorders (11,12). The possible isolation of sEVs from almost every biological fluid and the recent methodological advancement to isolate cell type-specific sEVs pose them as an attractive target for the development of non/less invasive biomarkers for complicated diseases like psychiatric disorders. Analyzing the cargos of neuron-derived EVs (NDEVs) have been shown to predict the development of Alzheimer’s disease (AD) up to 10 years before the clinical onset (13). Ledreux et al. reported that the NDEVs isolated from the individuals with Down syndrome and AD are loaded with p-Tau and have the tau seeding capacity to spread tau pathology in the mouse brain (14). Recently, our group also reported the utility of NDEVs and other brain cell-derived EVs in identifying the neurodegenerative and pro-inflammatory effects of oxycodone self-administration in cynomolgus monkeys (15).