Glia-derived Extracellular Vesicles in motion at the neuron surface: involvement of the prion protein

Extracellular Vesicles (EVs) shed from the plasma membrane of glia cells are key players in glia-neuron communication in healthy and diseased brain. By exposing adhesion receptors, EVs can interact with specific cells and deliver complex "signals", including proteins, lipids and RNA between cells. Under pathological conditions EVs become vehicle for the transfer of pathogens. Indeed, EVs released in the brain have been described to contain misfolded proteins associated to neurodegenerative diseases such as scrapie prion protein (PrPSc), superoxide dismutase 1 (SOD1), α-synuclein, tau and amyloid-β (Aβ). In the past years we highlighted the role of EVs in the transcellular signalling in the brain. EVs from glial cells modulate synaptic transmission, stimulating excitatory transmission and impairing the inhibitory one. Moreover, we demonstrated the transfer of the miR146a-5p mediated by EVs from glial cells to neurons. EV-neuron contact is critical for EV signalling to neurons, as preventing EV-neuron interaction by cloaking phosphatidylserine (PS) residues on the EV surface, inhibited EV-mediated effects. Previous evidence in Alzheimer’s Diseases (AD) cellular models showed that small EVs storing misfolded proteins can be internalized and transferred between neurons through axonal projections. However, if the diffusion of pathogenic proteins mediated by small EVs has been quite investigated, almost nothing is known about how large EVs can interact with neurons and reach preferential sites.