Increased Type I interferon signaling and brain endothelial barrier dysfunction in an experimental model of Alzheimer’s disease
Open accessAbstract
Blood–brain barrier (BBB) dysfunction is emerging as a key pathogenic factor in the progression of Alzheimer’s disease (AD), where increased microvascular endothelial permeability has been proposed to play an important role. However, the molecular mechanisms leading to increased brain microvascular permeability in AD are not fully understood. We studied brain endothelial permeability in female APPswe/PS1∆E9 (APP/PS1) mice which constitute a transgenic mouse model of amyloid-beta (Aβ) amyloidosis and found that permeability increases with aging in the areas showing the greatest amyloid plaque deposition. We performed an unbiased bulk RNA-sequencing analysis of brain endothelial cells (BECs) in female APP/PS1 transgenic mice. We observed that upregulation of interferon signaling gene expression pathways in BECs was among the most prominent transcriptomic signatures in the brain endothelium. Immunofluorescence analysis of isolated BECs from female APP/PS1 mice demonstrated higher levels of the Type I interferon-stimulated gene IFIT2. Immunoblotting of APP/PS1 BECs showed downregulation of the adherens junction protein VE-cadherin. Stimulation of human brain endothelial cells with interferon-β decreased the levels of the adherens junction protein VE-cadherin as well as tight junction proteins Occludin and Claudin-5 and increased barrier leakiness. Depletion of the Type I interferon receptor in human brain endothelial cells prevented interferon-β-induced VE-cadherin downregulation and restored endothelial barrier integrity. Our study suggests that Type I interferon signaling contributes to brain endothelial dysfunction in AD.
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Stimulation of endothelial cells with Aβ or proinflammatory cytokines reduced expression of tight junction proteins Claudin-5, VE-cadherin and Occludin, thus increasing permeability.
“Multiple in vitro experiments revealed that stimulation of endothelial cells with Aβ or proinflammatory cytokines reduced the expression of tight junction proteins like Claudin-5, VE-cadherin and Occludin, thus increased permeability.474–478”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [476]
The Results section reports that IFN-β treatment of human brain endothelial cells reduced VE-cadherin, Occludin and Claudin-5 and increased permeability. It does not report an in vitro experiment stimulating those cells directly with Aβ; it also identifies VE-cadherin as an adherens-junction protein, not a tight-junction protein. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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- Authors
- Jana, A., Wang, X., Leasure, J. W., Magana, L., Wang, L., Kim, Y.-M., Dodiya, H., Toth, P. T., Sisodia, S. S., & Rehman, J.
- Affiliations
- University of Illinois Chicago (US)
- University of Chicago (US)
- Corresponding author
- Rehman, Jalees
- ORCID
- Venue
- Scientific Reports
- Published
- 2022-10-01
- Volume
- 12
- Issue
- 1
- Pages
- 16488-16488
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC9526723
- OpenAlex
- W4298394214
- Cited by
- 43
- References
- 76
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 14 · 2023: 7
- FWCI
- 3.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (HL060678, HL007829)
- National Heart, Lung, and Blood Institute (T32HL139439, P01HL060678, R01HL152515, T32HL007829)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, blood-brain barrier dysfunction, brain endothelial cells, type I interferon signaling, interferon-beta, amyloid-beta, APP/PS1 mice, endothelial permeability, VE-cadherin, tight junctions, IFIT2, interferon receptor, aging, amyloid plaques
- MeSH terms
- Alzheimer Disease, Animals, Blood-Brain Barrier, Brain, Disease Models, Animal, Endothelium, Female, Humans, Interferon Type I, Mice, Transgenic, RNA, Amyloid beta-Peptides, Interferon-beta, Endothelial Cells, Mice, Receptor, Interferon alpha-beta, Plaque, Amyloid, Claudin-5, Tight Junction Proteins, Occludin
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