The DOI matches its Crossref record; 105 of the 105 references it cites were found in a registry or an index.
Microglial large extracellular vesicles propagate early synaptic dysfunction in Alzheimer’s disease
Open accessAbstract
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 amyloid-β 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. One hour after Aβ-EV injection into the mouse entorhinal cortex, long-term potentiation was impaired in the entorhinal cortex but not in the dentate gyrus, its main target region, while 24 h later it was also impaired in the dentate gyrus, revealing a spreading of long-term potentiation deficit between the two regions. Similar results were obtained upon injection of extracellular vesicles carrying Aβ naturally secreted by CHO7PA2 cells, while neither Aβ42 alone nor inflammatory extracellular vesicles devoid of Aβ were able to propagate long-term potentiation 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 long-term potentiation deficit occurred along the entorhinal–hippocampal circuit, implicating large extracellular vesicle motion at the neuron surface in the spreading of long-term potentiation impairment. Our data indicate the involvement of large microglial extracellular vesicles in the rise and propagation of early synaptic dysfunction in Alzheimer’s disease and suggest a new mechanism controlling the diffusion of large extracellular vesicles and their pathogenic signals in the brain parenchyma, paving the way for novel therapeutic strategies to delay the disease.
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“Microglia could also lead to synaptic dysfunction in vivo and in vitro by releasing Aβ-containing EVs.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [198]
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Ranaldi, E. D. L. R. M. C., Johnson, N. H., Sawaya, A. P., Herrera, J. R., Kerr, N. A., Bramlett, H. M., Keane, R. W., Dietrich, W. D., & Vaccari, J. P. D. R. (2026) · Cells · doi:10.3390/cells15181658
Extracellular vesicles: Multi-source regulatory mechanisms in hippocampal homeostasis
Liu, Q., & Guo, L. (2026) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2026.107015
李红涛, Yin, T., Wang, Y., Wang, Y., Lin, X., Jia, X., Yi, W., & Yang, H. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1952469
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Sun, J., Gao, G., Wang, S., Li, S., Tang, J., Liu, H., & Tang, T.-S. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02776-4
Metadata
- Authors
- 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., & Verderio, C.
- Affiliations
- CNR Institute of Neuroscience , Vedano al Lambro, MB 20854 , Italy
- Neuroscience Institute (IT)
- Scuola Superiore Sant'Anna (IT)
- University of Milano-Bicocca (IT)
- University of Brescia (IT)
- Scuola Normale Superiore (IT)
- Consorzio Interuniversitario per lo Sviluppo dei Sistemi a Grande Interfase (IT)
- Columbia University (US)
- Corresponding author
- Origlia, Nicola
- Verderio, Claudia
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-03-03
- Volume
- 145
- Issue
- 8
- Pages
- 2849-2868
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC9420022
- OpenAlex
- W4214920994
- Cited by
- 106
- References
- 105
- Citations by year
- 2026: 22 · 2025: 29 · 2024: 27 · 2023: 22 · 2022: 6
- FWCI
- 12.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion, cc-by-nc)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion, cc-by-nc)
- Scuola Normale Superiore di Pisa (submittedVersion, cc-by-nc)
- Funders
- American National Institutes of Health (1R56AG056108-01)
- Alzheimer’s Association Research Fellowship (2018-AARF-588984)
- Italian Multiple Sclerosis Foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, microglia, large extracellular vesicles, amyloid-beta, synaptic dysfunction, long-term potentiation, dendritic spine morphology, synaptic plasticity, vesicle motility, annexin V, amyloid-beta 42, disease propagation
- MeSH terms
- Extracellular Vesicles, Alzheimer Disease, Animals, Hippocampus, Amyloid beta-Peptides, Microglia, Long-Term Potentiation, Mice
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