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Neuroscience. 2015 Jun 4;295:11-22. doi: 10.1016/j.neuroscience.2015.03.023. Epub 2015 Mar 19.

Fibrillin-1 impairment enhances blood-brain barrier permeability and xanthoma formation in brains of apolipoprotein E-deficient mice.

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Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
Department of Pathology M2-206, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Laboratory of Cell Biology and Histology, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium.
Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, UZ Herestraat 49 - bus 911, 3000 Leuven, Belgium.
Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address:


We recently reported that apolipoprotein E (ApoE)-deficient mice with a mutation in the fibrillin-1 gene (ApoE(-/-)Fbn1(C1039G+/-)) 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 blood-brain barrier (BBB). Here, we investigated whether fibrillin-1 impairment affects the permeability of the BBB proper and the blood-cerebrospinal fluid barrier (BCSFB), and whether this leads to the accelerated accumulation of lipids (xanthomas) in the brain. ApoE(-/-) (n=61) and ApoE(-/-)Fbn1(C1039G+/-) (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(-/-)Fbn1(C1039G+/-) 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(-/-)Fbn1(C1039G+/-) 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.


blood–brain barrier; choroid plexus; fibrillin-1; xanthomas

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