Astrocytes contribute to Aβ‐induced blood–brain barrier damage through activation of endothelial MMP 9
Abstract
The blood–brain barrier ( BBB ) plays an important role in the maintenance of the brain homeostasis, and its proper functions are warranted by the interplay between different cellular components (endothelial cells, astrocytes and pericytes). BBB dysfunctions in pathological conditions, and particularly in Alzheimer's disease, have been documented. Here, using an in vitro BBB model, the interaction between endothelial cells and astrocytes exposed to Aβ1‐42 was investigated. Human endothelial cells, cultured in monolayer or co‐cultured with astrocytes, were exposed to Aβ1‐42 (2 μM for 18 h). Aβ induced dysfunction of endothelial barrier, as assessed by enhanced permeability to FITC ‐conjugated dextran and reduced expression of claudin‐5; these modifications were observed in the co‐culture model, but not in endothelial cells cultured in monolayer. Similarly, Aβ‐induced damage at the barrier was observed when endothelial cells were challenged in the presence of conditioned medium generated by astrocytes previously exposed to Aβ ( ACM Aβ). Endothelial barrier damages were associated with enhanced matrix metalloprotease 9 ( MMP 9) activity, known to mediate claudin‐5 disruption. These events were not related to the direct effects played by Aβ on endothelial cells, but they were rather the consequence of Aβ‐induced vascular endothelial growth factor (VEGF) expression in astrocytes. Indeed, when vascular endothelial growth factor expression was down‐regulated in astrocytes, neither barrier properties or MMP 9 expression in endothelial cells were affected after Aβ exposure both in the co‐culture model or in the presence of ACM Aβ. These data point out the importance of astrocytes’ mediation in inducing endothelial sensitivity to Aβ1‐42 . image
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The breakdown of claudin-5 can be attributed to VEGF-mediated MMP expression.
“several studies in ischaemic stroke, a neurological disease characterized by BBB impairment, suggest that the breakdown of claudin-5 can be attributed to VEGF-mediated matrix metalloproteinase (MMP) expression [52–55].”
From Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain (2022) · cites this paper as [55]
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- Authors
- Spampinato, S. F., Merlo, S., Sano, Y., Kanda, T., & Sortino, M. A.
- Affiliations
- University of Catania (IT)
- Yamaguchi University (JP)
- Corresponding author
- Sortino, Maria Angela
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2017-06-20
- Volume
- 142
- Issue
- 3
- Pages
- 464-477
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2613908362
- Cited by
- 90
- References
- 57
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 6 · 2023: 8 · 2022: 15 · 2021: 11 · 2020: 12 · 2019: 11 · 2018: 8 · 2017: 2
- FWCI
- 4.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- Maria Angela Sortino (20130143075)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- astrocytes, amyloid-beta, blood-brain barrier, endothelial cells, MMP-9, claudin-5, vascular endothelial growth factor, Alzheimer's disease, endothelial permeability, astrocyte-endothelial interactions, conditioned medium
- MeSH terms
- Astrocytes, Biological Transport, Blood-Brain Barrier, Capillary Permeability, Cells, Cultured, Enzyme Activation, Humans, Amyloid beta-Peptides, Culture Media, Conditioned, Tight Junctions, Matrix Metalloproteinase 9, Vascular Endothelial Growth Factor A, Endothelial Cells
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