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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.

Author information

1
Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
2
Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
3
Department of Pathology M2-206, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
4
Laboratory of Cell Biology and Histology, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium.
5
Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, UZ Herestraat 49 - bus 911, 3000 Leuven, Belgium.
6
Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address: guido.demeyer@uantwerpen.be.

Abstract

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.

KEYWORDS:

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

[Indexed for MEDLINE]

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