Extracellular Vesicle-Mediated Neuron-Glia Communications in the Central Nervous System

Abstract

Communication between neurons and glia significantly influences the development maturation, plasticity, and disease progressions of the nervous system. As a new signaling modality, extracellular vesicles display a diverse role for robust functional regulation of neurons through their protein and nucleic acid cargoes. This review highlights recent breakthroughs in the research of signaling mechanisms between glia and neurons mediated by extracellular vesicles that are important for neural development, axonal maintenance, synaptic functions, and disease progression in the mammalian nervous system. We will discuss the biological roles of extracellular vesicles released from neurons, astroglia, microglia, and oligodendroglia in the nervous system and their implications in neurodegenerative disorders.

Keywords: Alzheimer’s disease; astrocytes; axonal integrity; extracellular vesicles; intercellular communication; microglia; multivesicular bodies; neurodegenerative disorders; oligodendrocytes; synaptic transmission; tauopathy.

Figure 1.

Intercellular communication of CNS cells via EVs. EVs carry multiple species of molecules, including lipids, nucleic acids (DNA and RNA) and proteins including misfolded proteins. EV-mediated transfer of proteins and nucleic acids has been shown to occur between neurons and astroglia, microglia and oligodendrocytes, and misfolded proteins between neurons and microglia to neurons. Arrows indicate distinct EV-mediated signaling pathways between CNS cells. The CNS EV cargo is representative of the donor cell and may be detected as biomarker if carried to peripheral biofluids, assisting decoding of disease states and mechanisms.

Figure 2.

Extracellular vesicle (EV)-mediated signaling between astroglia and neurons. Astroglia can secrete both large EVs (microvesicles) and small EVs (exosomes) to significantly modulate neuronal development and activity, including excitability, dendritic arborization, and axon growth. Several signals, including ATP, cytokines, and glycerophosphodiester phosphodiesterase 3 (GDE3), have been shown to regulate EV secretion from astroglia, though the exact location of release (soma vs process) remains unclear.

Figure 3.

EV-mediated propagation of misfolded tau protein in the CNS. In AD, misfolded tau protein can be transmitted through a trans-synaptic pathway either in soluble or EV-contained forms. Accumulation of misfolded tau inactivates synapses, which are subject of synaptic pruning by microglia. Undigested tau seeds are secreted as either soluble or EV-contained form from microglia in P2RX7 sensitive manner.

Figure 4.

Extracellular and intracellular trafficking of microglial EVs carrying misfolded Aβ/tau proteins across the synapse. Large Aβ-EVs produced by microglia transfer Aβ cargo across the synapse by moving at the surface of axonal projection and affect LTP. Microglia-derived small tau-EVs are taken up by neurons into endosomes, which can fuse with MVBs generating hybrid secretory endosomes. These hybrid MVBs are transported anterogradely inside axons and mediate the release of internalized microglial small tau-EVs along with endogenous small EVs upon fusion with the presynaptic membrane. Transcytosis of tau-EVs promotes impairment of neuronal function.

Figure 5.

Functions of oligodendrocyte-derived EVs in axonal maintenance. Myelin produced by oligodendrocytes provides electrical isolation and prevents the uptake of nutrients and other extracellular interactions by axons. Oligodendrocyte-derived EVs support axons by providing biomolecules that are important for basic axonal functions and provide a pathway for external supply. Oligodendrocyte-derived EVs (exosomes) are released from periaxonal MVBs in response to neuronal activity and glutamatergic axon-to-myelin signaling. Exosomes are internalized by neurons and provide essential support for the maintenance of axonal integrity by increasing ATP availability, providing antioxidant defense, and promoting axonal transport. SIRT2 and FTH1 are relevant exosome cargos improving mitochondrial ATP production and protecting cells from ferroptotic damage, respectively. MVB, multivesicular body, ROS, reactive oxygen species, FTH1, Ferritin heavy chain 1.