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Title
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Fibrillin-1 impairment enhances bloodbrain barrier permeability and xanthoma formation in brains of apolipoprotein E-deficient mice
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Author
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Abstract
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| 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. |
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Language
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English
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Source (journal)
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Neuroscience / International Brain Research Organization. - Oxford
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Publication
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Oxford
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2015
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ISSN
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0306-4522
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DOI
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10.1016/J.NEUROSCIENCE.2015.03.023
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Volume/pages
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295
(2015)
, p. 11-22
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ISI
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000353208100002
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Full text (Publisher's DOI)
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Full text (open access)
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Full text (publisher's version - intranet only)
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