Title
Fibrillin-1 impairment enhances bloodbrain barrier permeability and xanthoma formation in brains of apolipoprotein E-deficient mice Fibrillin-1 impairment enhances bloodbrain barrier permeability and xanthoma formation in brains of apolipoprotein E-deficient mice
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
Oxford ,
Subject
Biology
Pharmacology. Therapy
Human medicine
Source (journal)
Neuroscience / International Brain Research Organization. - Oxford
Volume/pages
295(2015) , p. 11-22
ISSN
0306-4522
ISI
000353208100002
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
We recently reported that apolipoprotein E (ApoE)-deficient mice with a mutation in the fibrillin-1 gene (ApoE−/−Fbn1C1039G+/−) develop accelerated atherosclerosis with enhanced inflammation, atherosclerotic plaque rupture, myocardial infarction and sudden death. In the brain, fibrillin-1 functions as an attachment protein in the basement membrane, providing structural support to the bloodbrain barrier (BBB). Here, we investigated whether fibrillin-1 impairment affects the permeability of the BBB proper and the bloodcerebrospinal fluid barrier (BCSFB), and whether this leads to the accelerated accumulation of lipids (xanthomas) in the brain. ApoE−/− (n = 61) and ApoE−/−Fbn1C1039G+/− (n = 73) mice were fed a Western-type diet (WD). After 14 weeks WD, a significantly higher permeability of the BBB was observed in ApoE−/−Fbn1C1039G+/− mice compared to age-matched ApoE−/− mice. This was accompanied by leukocyte infiltration, enhanced expression of pro-inflammatory cytokines, matrix metalloproteinases and transforming growth factor-β, and by decreased expression of tight junction proteins claudin-5 and occludin. After 20 weeks WD, 83% of ApoE−/−Fbn1C1039G+/− mice showed xanthomas in the brain, compared to 23% of their ApoE−/− littermates. Xanthomas were mainly located in fibrillin-1-rich regions, such as the choroid plexus and the neocortex. Our findings demonstrate that dysfunctional fibrillin-1 impairs BBB/BCSFB integrity, facilitating peripheral leukocyte infiltration, which further degrades the BBB/BCSFB. As a consequence, lipoproteins can enter the brain, resulting in accelerated formation of xanthomas.
E-info
https://repository.uantwerpen.be/docman/iruaauth/3b111c/9057dae6726.pdf
Full text (open access)
https://repository.uantwerpen.be/docman/irua/d850c0/9814.pdf
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