Exosomes: Origins and Therapeutic Potential for Neurodegenerative Disease

Abstract

Exosomes, small lipid bilayer vesicles, are part of the transportable cell secretome that can be taken up by nearby recipient cells or can travel through the bloodstream to cells in distant organs. Selected cellular cytoplasm containing proteins, RNAs, and other macromolecules is packaged into secreted exosomes. This cargo has the potential to affect cellular function in either healthy or pathological ways. Exosomal content has been increasingly shown to assist in promoting pathways of neurodegeneration such as β-amyloid peptide (Aβ) accumulation forming amyloid plaques in the brains of patients with Alzheimer's disease, and pathological aggregates of proteins containing α-synuclein in Parkinson's disease transferred to the central nervous system via exosomes. In attempting to address such debilitating neuropathologies, one promising utility of exosomes lies in the development of methodology to use exosomes as natural delivery vehicles for therapeutics. Because exosomes are capable of penetrating the blood-brain barrier, they can be strategically engineered to carry drugs or other treatments, and possess a suitable half-life and stability for this purpose. Overall, analyses of the roles that exosomes play between diverse cellular sites will refine our understanding of how cells communicate. This mini-review introduces the origin and biogenesis of exosomes, their roles in neurodegenerative processes in the central nervous system, and their potential utility to deliver therapeutic drugs to cellular sites.

Keywords: biogenesis; exosomes; nanotherapeutics; neurodegeneration.

Figure 1

Exosome Biogenesis. Cytoplasmic cargo is selected by sorting mechanisms (as yet not comprehensively elucidated) and placed into early endosomes. The endosomes may then enter the lysosomal degradation pathway where the exosome contents are degraded and recycled for cellular use or removed as debris. In the second pathway, the endosome forms a multivesicular body (MVB) containing many intraluminal vesicles (ILVs). The MVB can deliver the ILV to the plasma membrane where they are extruded and become exosomes. These exosomes may act as cell to cell messengers to nearby recipient cells or be picked up in the circulation from the extracellular space. Consequently, exosomes may affect distant cellular sites by being captured at their plasma membranes by receptor-ligand interactions. See references (Keller et al., ; Trajkovic et al., ; Colombo et al., ; Kowal et al., ; Hurley, 2015) for further detail.

Figure 2

Exosome Content. Exosomes are a bilayer lipid membrane that encapsulate cellular cargo selected from the cytoplasm by sorting mechanisms. The lipid membrane may also contain ligands for recipient cell receptors at near or distant systemic sites. Cataloged in exocarta.org is a list of commonly found proteins and RNAs in exosomes. Recent analyses of exosomes from neurodegenerative cells have documented disease-associated cargoes in the exosomes. For further details see references (Bellingham et al., ,; Taylor and Shah, ; Benussi et al., ; Willms et al., 2016).

Figure 3

Exosomes as carriers of therapeutics. It is proposed that natural or synthetic exosomes could be used as therapeutic tools because the lipid-bound vesicles resist degradation. They are shown to carry and deliver cargo via a secretome from one cell to another. Exosomes have the unusual ability to cross the blood-brain barrier and therefore present a unique opportunity to deliver therapeutics to targeted brain regions. See references (Lamichhane et al., ; Lener et al., ; Aryani and Denecke, ; Lopez-Verrilli et al., ; Yim and Choi, 2016) for further detail.