The Role of Extracellular Vesicles in Demyelination of the Central Nervous System

Abstract

It is being increasingly demonstrated that extracellular vesicles (EVs) are deeply involved in the physiology of the central nervous system (CNS). Processes such as synaptic activity, neuron-glia communication, myelination and immune response are modulated by EVs. Likewise, these vesicles may participate in many pathological processes, both as triggers of disease or, on the contrary, as mechanisms of repair. EVs play relevant roles in neurodegenerative disorders such as Alzheimer's or Parkinson's diseases, in viral infections of the CNS and in demyelinating pathologies such as multiple sclerosis (MS). This review describes the involvement of these membrane vesicles in major demyelinating diseases, including MS, neuromyelitis optica, progressive multifocal leukoencephalopathy and demyelination associated to herpesviruses.

Keywords: central nervous system; demyelination; extracellular vesicles; herpesviruses; multiple sclerosis; neuromyelitis optica; progressive multifocal leukoencephalopathy.

Figure 1

Major demyelinating diseases of the central nervous system (CNS). The major demyelinating inflammatory CNS disorder is multiple sclerosis (MS), a progressive autoimmune disease of unknown etiology. There are other idiopathic inflammatory-demyelinating diseases (IIDDs) such as optic neuritis, neuromyelitis optica and transverse myelitis. Another IIDD is acute disseminated encephalomyelitis (ADEM), an inflammatory autoimmune disorder with a likely infectious etiology. Acute hemorrhagic leukoencephalitis (AHL), a variant of ADEM, is possibly elicited by an infectious trigger. Other demyelinating CNS diseases have an identified etiology, such as viral infections, for instance, subacute sclerosing panencephalitis (SSPE) or progressive multifocal leukoencephalopathy (PML), immunological mechanisms, toxins, metabolic disorders or ischemia.

Figure 2

Schematic diagrams depicting the implication of extracellular vesicles (EVs) in MS. (A) MVs secreted by endothelial cells, immune cells and platelets are increased in the plasma of MS patients compared to healthy controls. These MVs contribute to blood–brain barrier (BBB) disruption and endothelial injury in these patients. (B) MVs isolated from the cerebrospinal fluid (CSF) of MS patients are increased compared to controls. These EVs are enriched in membrane attack complex (MAC) components and platelet-endothelial cell adhesion molecule-1 (PECAM-1). (C) Circulating exosomes have a different miRNA profile in MS patients.

Figure 3

Schematic diagrams depicting the implication of EVs in other CNS demyelinating diseases. Analysis of the CSF of neuromyelitis optica (NMO) patients has shown a distinct exosomal profile (A) and an increase in astrocytic aquaporin-4 (AQP4)-positive microvesicles (MVs) (B) in these patients compared to healthy controls. (C) JCV, the virus associated with the etiology of progressive multifocal leukoencephalopathy (PML), may be secreted enclosed in exosomes that can infect target cells independently of viral receptors. (D) Herpes simplex virus type 1 (HSV-1), another virus implicated in demyelination, may also be spread enclosed in MVs. Transmission electron micrograph shows a HSV-1 virion enclosed in a double-membraned MV, and is thus covered by three lipid membrane layers.