Venue: Centre Broca
Institute of Neurosciences, Milan, Italy
Invited by Rebecca Hekking (Oliet’s team – Magendie)
Microglial EVs travelling at the neuron surface: implication in synaptic pruning and abeta-related synaptic dysfunction
Using optical tweezers combined to time-lapse imaging, we studied EV-neuron interaction dynamics in vitro coming to the unexpected observation that a large fraction of glial EVs move along the surface of hippocampal neurons, scanning actin protrusions (D’Arrigo et al., JEV 2021; Gabrielli et al., Brain 2022). In fully differentiated cultures, EVs frequently stop moving at synaptic sites on dendrites, while the fraction of moving EVs and average EV motion are elevated along axons. These data, together with previous evidence showing that microglial EVs carry multiple signals implicated in synaptic pruning (PS, complement factors), prompted us to investigate whether EVs may deliver molecules guiding microglia-mediated synaptic removal on dendrites and exploit axonal projections as highways to reach target neurons to spread pathological signals across the synapse. In my talk I go in deep into our research on these topics.
The hypothesis that EVs may use axons to move between synaptically connected neurons and spread their cargo was tested in a neurodegenerative context. According to our data, the injection of large microglial EVs carrying Aβ species (Aβ-EVs) induces and propagates amyloid-related synaptic deficits among synaptically connected regions in a circuit primarily affected in Alzheimer’s disease (AD), i.e. the entorhinal-hippocampal circuit, leading to progressive memory impairment and persistent network alterations both at hippocampal and cortical level (Gabrielli et. al, Brain, 2022; Falcicchia et al, Brain Comm, 2023). When the motility of Aβ-EVs is inhibited, there is no synaptic dysfunction propagation nor network stability impairment. These data unveil motion of large Aβ-EVs at the neuron surface as a new mechanism contributing to the diffusion of Aβ-related pathology in AD.
To explore EV involvement in synaptic pruning, we co-cultured neurons with wild type (wt) or mutant (C9orf72 knock out) microglia, which produce more EVs and complement factors compared to wt, and analyzed synaptic density, finding that mutant microglia enhance engulfment of pre-synaptic material. Interestingly, pretreatment of mutant microglia with GW4869, an inhibitor of EV biogenesis, restored normal pre-synaptic density, while supplementation of microglial EVs to neurons decreased pre-synaptic density and favored engulfment of synaptic material/synaptosomes by microglia, revealing that EVs promote synaptic pruning. Immunofluorescence analysis of C9orf72 ko hippocampi at P17 (peak synaptic pruning) showed lower density of Vglut+ pre-synapses and revealed higher C1q staining in CA1 area compared to wt, linking larger EV production to enhanced C1q deposition and excessive pruning.
Our studies shed light on the possible roles of microglial EVs in synaptic alterations in neurodevelopmental and neurodegenerative disorders.
D’Arrigo G, Gabrielli M, Scaroni F, Swuec3 P, Amin L, Pegoraro A, Adinolfi E, Di Virgilio F, Cojoc D, Legname G, Verderio C (2021) Astrocytes-derived extracellular vesicles in motion at the neuron surface: involvement of the prion protein. JEV, Jul;10(9):e12114.
Gabrielli M, Prada I, Joshi P, Falcicchia C, D’Arrigo G, Rutigliano G, Battocchio E, Zenatelli R, Tozzi F, Radeghieri A, Arancio O, Origlia N* and Verderio C* (2022) Microglial large extracellular vesicles propagate early synaptic dysfunction in Alzheimer’s disease. Brain, 45(8):2849-2868.
Falcicchia C, Tozzi F, Gabrielli M, Amoretti S, Masini G, Nardi G, Guglielmo S, Ratto GM, Arancio O, Verderio C*, Origlia N* (2023)(*co-corresponding author). Microglial extracellular vesicles induce Alzheimer’s disease-related cortico-hippocampal network dysfunction. Brain Commun. May 31;5(3): fcad170. doi: 10.1093/braincomms/fcad170.
PhD seminars are organized by the NBA, Bordeaux Neurocampus, and the Bordeaux Neurocampus Graduate Program