Small but Mighty-Exosomes, Novel Intercellular Messengers in Neurodegeneration

Exosomes of endosomal origin are one class of extracellular vesicles that are important in intercellular communication. Exosomes are released by all cells in our body and their cargo consisting of lipids, proteins and nucleic acids has a footprint reflective of their parental origin. The exosomal cargo has the power to modulate the physiology of recipient cells in the vicinity of the releasing cells or cells at a distance. Harnessing the potential of exosomes relies upon the purity of exosome preparation. Hence, many methods for isolation have been developed and we provide a succinct summary of several methods. In spite of the seclusion imposed by the blood-brain barrier, cells in the CNS are not immune from exosomal intrusive influences. Both neurons and glia release exosomes, often in an activity-dependent manner. A brief description of exosomes released by different cells in the brain and their role in maintaining CNS homeostasis is provided. The hallmark of several neurodegenerative diseases is the accumulation of protein aggregates. Recent studies implicate exosomes’ intercellular communicator role in the spread of misfolded proteins aiding the propagation of pathology.

Researchers from Kansas State University discuss the potential contributions made by exosomes in progression of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Understanding contributions made by exosomes in pathogenesis of neurodegeneration opens the field for employing exosomes as therapeutic agents for drug delivery to brain since exosomes do cross the blood-brain barrier.

Cellular events related to biogenesis and release of exosomes from the cell

Pinocytosis, clathrin (bristle-coated)-mediated and clathrin-independent endocytosis phosphate) from the trans-Golgi network and phagosomes (not shown here). The lumen of late endosomes becomes acidic due to the progressive concentration of ATP-driven H+ pumps in the vesicle membrane. Acidification is a complex phenomenon not completely understood. If the pH in the lumen is below 6, then late endosomes fuse with lysosomes for degradation and recycling of their content. However, if the pH in the lumen of late endosome is above 6, then they escape fusion with lysosomes and subsequent hydrolysis. During maturation of early endosomes to late endosomes, intraluminal vesicles arise from inward invaginations of the internal membrane. RNAs, proteins, and lipids are incorporated into developing intraluminal vesicles through ESCRT-dependent and ESCRT-independent mechanisms. Late endosomes packed with intraluminal vesicles have a multivesicular appearance and are identified as multivesicular bodies. They migrate towards and fuse with the plasma membrane to release their intraluminal vesicles, i.e., exosomes into the extracellular space. Nuclear blebbing appears to generate structures similar to multivesicular bodies (here referred to as MVB type II) that eventually detach from the nuclear membrane and become cytosolic. The MVB type II packed with RNA and/or genomic DNA may receive RNA-binding proteins from the nucleus and/or the trans-Golgi network and fuse with early/late endosomes to export their intraluminal vesicles into the extracellular space.