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Cited by 37Extracellular vesicles in diseaseAlzheimer's disease research and treatmentsBarrier Structure and Function Studies

Extracellular Vesicles From 3xTg-AD Mouse and Alzheimer’s Disease Patient Astrocytes Impair Neuroglial and Vascular Components

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González-Molina, Luis Alfonso, Villar-Vesga, Juan, Henao-Restrepo, Julián, Villegas, Andrés, Lopera, Francisco, Cardona-Gómez, Gloria Patricia, Posada-Duque, Rafael·2021·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2021.593927PMC PMC7933224
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Abstract

Astrocytes are specialized glial cells that are essential components of the neurovascular unit (NVU) and are involved in neurodevelopment, brain maintenance and repair, and neurodegeneration. Astrocytes mediate these processes by releasing cellular mediators such as extracellular vesicles (EVs). EVs are vehicles of cell-cell communication and have been proposed as mediators of damage in AD. However, the transcellular mechanism by which Alzheimer disease (AD) astrocytes impair the function of NVU components is poorly understood. Therefore, we evaluated the effects of adult PS1-KI and 3xTg-AD astrocyte conditioned media (CM) and EVs on NVU components (neuroglia and endothelium) in vitro . Additionally, SAD and FAD astrocyte-derived EVs (A-EVs) were characterized, and we evaluated their effects on NVU in cocultured cells in vitro and on intrahippocampal CA1 cells in vivo . Surprisingly, cultured 3xTg-AD astrocytes showed increased glial fibrillary acidic protein (GFAP) reactivity compared to PS1-KI astrocytes, which denotes astrocytic hyperreactivity. CM from adult mice 3xTg-AD astrocytes increased cell-cell gaps between endothelial cells, filopodia-like dendritic protrusions in neurons and neuronal and endothelial cell death. 3xTg-AD A-EVs induced neurotoxicity and increased astrocyte GFAP reactivity. Cultured human postmortem astrocytes from AD patients also increased GFAP reactivity and EVs release. No differences in the size or number of A-EVs were detected between AD and control samples; however, both SAD and FAD A-EVs showed increased expression of the surface marker aquaporin 4. A-EVs induced cytotoxicity and astrocyte hyperactivation: specifically, FAD A-EVs induced neuroglial cytotoxicity and increased gaps between the endothelium, while SAD A-EVs mainly altered the endothelium. Similarly, both AD A-EVs increased astrocyte GS reactivity and vascular deterioration in vivo . We associated this finding with perivascular reactive astrocytes and vascular deterioration in the human AD brain. In summary, these results suggest that AD A-EVs impair neuroglial and vascular components.

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Cited by

Sorted by citations

Authors
González-Molina, L. A., Villar-Vesga, J., Henao-Restrepo, J., Villegas, A., Lopera, F., Cardona-Gómez, G. P., & Posada-Duque, R.
Affiliations
Universidad de Antioquia (CO)
ORCID
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2021-02-19
Volume
13
Pages
593927-593927
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2021.593927
PMC
PMC7933224
OpenAlex
W3130748999
Cited by
37
References
18
Citations by year
2026: 7 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 12 · 2021: 4
FWCI
1.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Greater South Information System
Funders
Departamento Administrativo de Ciencia, Tecnología e Innovación
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
extracellular vesicles, Alzheimer's disease, astrocytes, neurovascular unit, 3xTg-AD mice, glial fibrillary acidic protein, aquaporin-4, endothelial cells, neurotoxicity, conditioned medium, intercellular communication

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