Emerging roles of extracellular vesicles in the nervous system

Abstract

Information exchange executed by extracellular vesicles, including exosomes, is a newly described form of intercellular communication important in the development and physiology of neural systems. These vesicles can be released from cells, are packed with information including signaling proteins and both coding and regulatory RNAs, and can be taken up by target cells, thereby facilitating the transfer of multilevel information. Recent studies demonstrate their critical role in physiological processes, including nerve regeneration, synaptic function, and behavior. These vesicles also have a sinister role in the propagation of toxic amyloid proteins in neurodegenerative conditions, including prion diseases and Alzheimer's and Parkinson's diseases, in inducing neuroinflammation by exchange of information between the neurons and glia, as well as in aiding tumor progression in the brain by subversion of normal cells. This article provides a summary of topics covered in a symposium and is not meant to be a comprehensive review of the subject.

Figure 1.

IL2 and male-specific B-type ciliated neurons release GFP-labeled EVs. Top panel, Diagram of six IL2 and 21 B-type sensory neurons in adult C. elegans male (in the head, four CEM neurons, and in the tail, one HOB and 16 RnB neurons). A, B, Male head and tail images of C. elegans polycystin-1 LOV-1::GFP reporter [N-terminal extracellular domain of LOV-1 (1–991 aa) fused to GFP]. In A–F, red arrows point to EVs surrounding the head and the tail. Insets, Framed area zoomed to 4×, and increased brightness to show GFP-labeled EVs. C, D, Male head and tail images of C. elegans polycystin-2 PKD-2::GFP reporter. Green arrowhead points to a CEM cilium with PKD-2::GFP enriched at the tip. Yellow arrows point to the cuticular pore of the ray neurons and PKD-2::GFP release around the pore. E, F, Coexpressed with polycystin protein CWP-1::GFP release from the head and the tail. G–J, Negatively stained EVs. G, EVs with no primary antibody control. H, I, J, Different images of LOV-1 antibody labeling endogenous LOV-1 on EVs purified from wild-type adult animals, detection by 0.8 nm ultrasmall gold, followed by silver enhancement. Scale bars: A–F, 10 μm; G–J, 100 nm. K, Model based on electron tomography of the distal end of the CEM neuron and its surroundings. The glial sheath cell and socket cell form a continuous lumen surrounding the CEM neuron cilium, which is exposed to the environment directly through a cuticular opening. The lumen is shared by CEM and CEP neurons. The CEM neuron is more centrally located in the lumen, while the CEP neuron is closer to the side of the lumen. EVs are observed in the cephalic lumen. Reproduced from Wang et al. (2014).

Figure 2.

Diagrammatic representation of the role of EVs in the release and uptake of amyloid proteins. Here PrPc, Aβ, Tau, and α-synuclein are shown as disease-related amyloid proteins. Aβ is derived from the proteolytic processing of the APP in early endosomes and is then retrogradely transported to MVBs. Once released in association with exosomes from the donor neurons, these proteins can be taken up in the recipient cells either via endocytosis or by direct penetration. Astrocytes and microglia might aid in the transmissibility. Adapted from Aguzzi and Rajendran (2009).

Figure 3.

Schematic representation of PMEL-derived amyloidogenesis. Within pigment cells, such as melanocytes, PMEL reaches MVEs from the plasma membrane (1). At the limiting membrane of the compartment, the PMEL luminal domain is released by BACE2 from its C-terminal fragment that is further cleaved by γ-secretase (2). The luminal domain of PMEL is sorted to ILVs by an unconventional sorting mechanism regulated by CD63 (3). At the surface of ILVs, PMEL domains aggregate into amyloid fibrils that accumulate in melanosomes (4). The fraction of ILVs that is secreted as exosomes in the extracellular medium is currently under investigation to better understand the formation of amyloid fibrils at their surface (5).

Figure 4.

The GBM tumor microenvironment. Glioblastoma cells grow interspersed within the normal brain parenchyma. The tumor cells interact with multiple different cell types, including astrocytes, neurons, oligodendrocytes, and microglia. Release of tumor-derived EVs alters the phenotype and transcriptome of recipient cells and enables the creation of a tumor-promoting environment. Normal cells also release vesicles, and their content may change in the context of the tumor. This figure was produced using Servier Medical Art (http://www.servier.com).