Role of extracellular vesicles in early synaptic dysfunction in AD. (1st February 2022)

• Record Type: Journal Article
• Authors: Gabrielli, Martina; D'Arrigo, Giulia; Falcicchia, Chiara; Origlia, Nicola; Arancio, Ottavio; Verderio, Claudia; Prada, Ilaria
• Is Part Of: Alzheimer's & dementia. Volume 17(2021)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-02-01
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.053488
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with amyloid‐β (Aβ) and tau protein accumulation. Synaptic dysfunction is an early mechanism in AD which involves progressively larger areas of the brain over time. However how synaptic dysfunction starts and propagates is unknown. The hypothesis we are testing is that large extracellular vesicles (EVs) released by microglia exposed to and carrying Aβ42 (Aβ‐EVs) may be responsible for these early events in AD. Method: Combining optical manipulation and time lapse imaging to place single large EVs on RFP‐positive cultured neuron dendrites or axons, we tested both their effects on the synapse and the dynamics of their interaction with neurons compared to ctrl‐EVs (released by microglia not exposed to Aβ42). Then, ctrl‐EVs, Aβ‐EVs or large EVs released by microglia exposed to CHO7PA2 cell supernatant containing naturally secreted Aβ oligomers (CHO‐EVs) were stereotaxically injected into the mouse entorhinal cortex (EC), one of the most vulnerable regions in AD, and long‐term potentiation (LTP) was measured in the EC and in his main target region, the dentate gyrus of the hippocampus (DG), through field potential extracellular recordings in cortico‐hippocampal brain slices. Result: Aβ‐EVs rapidly altered dendritic spine morphology, locally at the site of interaction, increasing the number of immature protrusions. After contact to the neuronal surface, Aβ‐EVs were able to move along the axonal surface more efficiently than ctrl‐EVs and predominantly in an anterograde direction. Furthermore, 1h after injection in the EC, LTP was impaired in the EC of brains injected with AβEVs, but not ctrl‐EVs. While 24h after AβEV injection, LTP was impaired also in the DG, indicating a spreading of synaptic dysfunction between the two connected regions. Importantly, we could reproduce these results by injection of CHO‐EVs. Conclusion: Our data indicate that Aβ‐EVs affect the synapse both in vitro and in vivo, and are able to propagate synaptic dysfunction among synaptically connected regions in vivo, providing evidence of the involvement of microglial large EVs in the onset and propagation of early synaptic dysfunction in AD, thus paving the way for novel therapeutic strategies. Funding: NIH1R56AG056108‐01 to OA and CV 2018‐AARF‐588984 to IP.