Extracellular vesicles as modulators of cell-to-cell communication in the healthy and diseased brain

Abstract

Homeostasis relies heavily on effective cell-to-cell communication. In the central nervous system (CNS), probably more so than in other organs, such communication is crucial to support and protect neurons especially during ageing, as well as to control inflammation, remove debris and infectious agents. Emerging evidence indicates that extracellular vesicles (EVs) including endosome-derived exosomes and fragments of the cellular plasma membrane play a key role in intercellular communication by transporting messenger RNA, microRNA (miRNA) and proteins. In neurodegenerative diseases, secreted vesicles not only remove misfolded proteins, but also transfer aggregated proteins and prions and are thus thought to perpetuate diseases by 'infecting' neighbouring cells with these pathogenic proteins. Conversely, in other CNS disorders signals from stressed cells may help control inflammation and inhibit degeneration. EVs may also reflect the status of the CNS and are present in the cerebrospinal fluid indicating that exosomes may act as biomarkers of disease. That extracellular RNA and in particular miRNA, can be transferred by EV also indicates that these vesicles could be used as carriers to specifically target the CNS to deliver immune modulatory drugs, neuroprotective agents and anti-cancer drugs. Here, we discuss the recent evidence indicating the potential role of exosomes in neurological disorders and how knowledge of their biology may enable a Trojan-horse approach to deliver drugs into the CNS and treat neurodegenerative and other disorders of the CNS.

Keywords: drug delivery; exosomes; extracellular vesicles; neurodegeneration; therapy.

Figure 1.

The role of extracellular vesicles in the healthy CNS. EVs carry signatures of the cell in question as well as specific EV-related factors. The impact of such release depends upon the cell type releasing the EVs and the cell type taking up the particles (see text for more details). (Online version in colour.)

Figure 2.

Extracellular vesicles in neurological disorders: proposed actions. In neurodegenerative disorders, neurons, and in some cases astrocytes, produce and release aggregated proteins such as α-synuclein, APP and phosphorylated tau and, in the case of prion disorders, pathogenic PrPSc protein. The EVs released may act as ‘seeds’ that spread the damage throughout the brain. In demyelinating disease, myelin-stressed oligodendrocytes produce altered myelin proteins and heat shock proteins (hsps) that may (hypothetically) be released in EVs. The ‘disease-associated’ proteins activate microglia that may augment disease or alternatively affect neurons and axons leading to dysfunction. (Online version in colour.)