Exosomes: Role in Cell Function, Neurodegeneration and Therapy

Since their isolation in 1983, cellular exosomes, small lipid bound 30-100 nm vesicles, have surprised researchers. Originally under appreciated and thought of as "cellular waste", it has become clear that the exosome plays an important regulatory role in communicating and altering cell signaling between neurons, astrocytes and microglia in the brain. The role exosomes may play in neurodegenerative diseases appears more complex than anticipated and remains largely undescribed. The biogenesis and content of these extracellular microvesicles is now known to impact cell function, locally and at distant sites in the body, by altering both normal and pathological processes. However, the mechanisms of cell-cell communication (targeting), exosome trafficking and exosome cargo selection remain to be characterized for each neuron type. Interest in exosome function has increased in the last several years due to the discovery that their cell-derived cargo contains many biomolecules (mRNA, miRNA, and protein) that may alter function by communicating an organ or cell’s disease status. Their role in cell-cell communication and demonstration that these biological particles can be used as biomarkers of disease is especially true in cancer research venues where they provide insights into the establishment of niche domains that promote metastatic processes. Exosomal cargo heterogeneity (likely distinct by cell type and disease state), small size and low yield from biological samples make isolation and study particularly difficult. In the central nervous system (CNS), neural exosome activity may bridge gaps in interneuron information exchange between neurons, astrocytes, oligodendrocytes and microglia. The exosome’s role in CNS disease, especially the progressive neurodegenerative diseases, e.g., Alzheimer’s and Parkinson’s, continues to unfold. While the functional role of exosomes is still under investigation, it is hypothesized that their release from cell to cell can drive healthy and pathological processes acting as either inhibitors or inducers of neural disease. They may play key roles in both regional brain development and neurodegeneration. Overall, exosomes offer the opportunity to capture new insights into the mechanisms of disease onset in the brain, to define biomarkers of specific diseases for early intervention and to create new modalities to therapeutically intervene in neurological diseases. As directed delivery vehicles, exosomes are proposed as lipid capsules engineered for therapeutic intervention for neurological diseases. They have a critical advantage over alternative therapeutic approaches because they can circulate un-degraded in the blood, cross the blood-brain barrier and communicate cargo (drugs) to selected target cells. Investigators are describing and cataloging exosome content (exo-lipids, exoRNA, exo-proteins) to understand biogenesis, trafficking and content delivery to cells.

This Research Topic focuses on neural exosomal cargo and function, the role of exosomes in interneuron cell communication and neurodegenerative diseases and, finally, the progress being made in using exosomes as therapeutic modalities to treat neurodegenerative disease.