Microglial large extracellular vesicles propagate early synaptic dysfunction in Alzheimer’s disease

Abstract

Synaptic dysfunction is an early mechanism in Alzheimer’s disease that involves progressively larger areas of the brain over time. However, how it starts and propagates is unknown. Here we show that Aβ released by microglia in association with large extracellular vesicles (Aβ-EVs) alters dendritic spine morphology in vitro, at the site of neuron interaction, and impairs synaptic plasticity both in vitro and in vivo in the entorhinal cortex-dentate gyrus circuitry. 1 h after Aβ-EV injection into the mouse entorhinal cortex, long-term potentiation (LTP) was impaired in the entorhinal cortex but not in the dentate gyrus, its main target region, while 24 h later it was impaired also in the dentate gyrus, revealing a spreading of LTP deficit between the two regions. Similar results were obtained upon injection of EVs carrying Aβ naturally secreted by CHO7PA2 cells, while neither Aβ42alone nor inflammatory EVs devoid of Aβ were able to propagate LTP impairment. Using optical tweezers combined to time-lapse imaging to study Aβ-EV-neuron interaction, we show that Aβ-EVs move anterogradely at the axon surface and that their motion can be blocked through annexin-V coating. Importantly, when Aβ-EV motility was inhibited, no propagation of LTP deficit occurred along the entorhinal-hippocampal circuit, implicating large EV motion at the neuron surface in the spreading of LTP impairment. Our data indicate the involvement of large microglial EVs in the rise and propagation of early synaptic dysfunction in Alzheimer’s disease, and suggest a new mechanism controlling the diffusion of large EVs and their pathogenic signals in the brain parenchyma, paving the way for novel therapeutic strategies to delay the disease.

Synovial Fluid-Derived Extracellular Vesicles of Patients with Arthritides Contribute to Hippocampal Synaptic Dysfunctions and Increase with Mood Disorders Severity in Humans

“…Finally, showing opposite changes at the excitatory and inhibitory levels in neurons treated with OA- and RA-EVs, this study lays the scientific basis for personalized medicine in OA and RA patients, hence in the presence of affective symptoms they should be treated with drugs that act through a different mechanism of action on glutamatergic or GABAergic synapse. Importantly, modifications here presented occur already within two hours, a temporal window that even if short, is coherent with previous studies displaying synaptic changes upon exogenous delivery of EVs to neurons [ 40 , 80 ]. Regarding the mechanism of action, our data identify the “EVs membrane” pellet as the principal factor actively involved and responsible for functional modifications here identified.…”

The multiple faces of extracellular vesicles released by microglia: Where are we 10 years after?

“…Finally, consistent with the formation of filopodia/spine head filopodia at the site of contacts between microglial processes and synapses ( Miyamoto et al, 2016 ; Weinhard et al, 2018a ), placement of single microglial large EVs on dendrites of cultured neurons by optical tweezers was recently shown to induce formation of filopodia/dendritic spine protrusions starting from 2 min after EV-neuron contacts ( Gabrielli et al, 2022 ), revealing that EVs mimic parental cell function.…”

“…Most studies used microglial EVs from in vitro rodent models, using both primary cultures [from C57BL/6 ( Kumar et al, 2017 ; Raffaele et al, 2021 ; Gabrielli et al, 2022 ) or CD-1 mice ( Asai et al, 2015 ; Ruan et al, 2020 ), Sprague-Dawley ( Antonucci et al, 2012 ; Gabrielli et al, 2015 ; Riganti et al, 2016 ; Drago et al, 2017 ; Prada et al, 2018 ; Lombardi et al, 2019 ) or Wistar rats ( Murgoci et al, 2020 )] and microglia cell lines [murine BV2 ( Hooper et al, 2012 ; Chang et al, 2013 ; Glebov et al, 2015 ; Kumar et al, 2017 ; Tian et al, 2019 ), N9 ( Bianco et al, 2005 ; Potolicchio et al, 2005 ), MG6 ( Takenouchi et al, 2015 )]. Rodent primary cultures are usually established from day 0 to 3 newborns or late stage (18–21 gestational days) embryos as mixed glia cultures.…”

“…EVs also represent a mechanism for microglia to dispose of waste products and other unwanted material, such as pathological misfolded proteins, which in fact are detected in EVs upon loading in microglia [amyloid beta (Aβ) ( Joshi et al, 2014 ; Gouwens et al, 2018 ; Gabrielli et al, 2022 ); tau protein ( Asai et al, 2015 ; Crotti et al, 2019 ); α-synuclein ( Fan et al, 2019 ; Xia et al, 2019 ; Guo et al, 2020 )]. This mechanism can also be exploited by pathogens (e.g., viral RNA; Luong and Olson, 2021 ) to move in tissues inside home-born shields.…”

Dynamics of Microglia Activation in the Ischemic Brain: Implications for Myelin Repair and Functional Recovery

“…Microglial EVs profoundly influence the molecular signature and function of recipient cells by activating contact-mediated signaling pathways (Antonucci et al, 2012 ; Gabrielli et al, 2015 ) and/or transferring genetic information (Drago et al, 2017 ; Prada et al, 2018 ). Recently, microglial EVs have been identified as mediators of inflammation and neurodegeneration (Verderio et al, 2012 ; Delpech et al, 2019 ; Gabrielli et al, 2022 ). On the other hand, they have been also described as vehicles of pro-regenerative molecules, directing OLs towards maturation (Lombardi et al, 2019 ), and modulating the activation state of microglia residing in the damaged tissue, resuming their protective functions (Casella et al, 2018 ; Zhang et al, 2020 ).…”