title: Fibrillin-1 impairment enhances blood-brain barrier permeability and xanthoma formation in brains of apolipoprotein E-deficient mice.
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.
authors: Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors: C
authors: C
authors: Van der Donckt
authors: Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors: L
authors: L
authors: Roth
authors: Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors: G
authors: G
authors: Vanhoutte
authors: Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors: I
authors: I
authors: Blockx
authors: Department of Pathology M2-206, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors: D I
authors: DI
authors: Bink
authors: Department of Pathology M2-206, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors: K
authors: K
authors: Ritz
authors: Laboratory of Cell Biology and Histology, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium.
authors: I
authors: I
authors: Pintelon
authors: Laboratory of Cell Biology and Histology, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium.
authors: J-P
authors: JP
authors: Timmermans
authors: Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, UZ Herestraat 49 - bus 911, 3000 Leuven, Belgium.
authors: D
authors: D
authors: Bauters
authors: Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors: W
authors: W
authors: Martinet
authors: Department of Pathology M2-206, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors: M J
authors: MJ
authors: Daemen
authors: Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors: M
authors: M
authors: Verhoye
authors: Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address: guido.demeyer@uantwerpen.be.
authors: G R Y
authors: GR
authors: De Meyer
mesh_terms: D000178:Acrylamides / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001812:Blood-Brain Barrier / Q000503:physiopathology* / Q000648:ultrastructure; D001921:Brain / Q000473:pathology*; D001927:Brain Diseases / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D005682:Gadolinium / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010539:Permeability; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014973:Xanthomatosis / Q000235:genetics / Q000473:pathology*; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000378:metabolism; D054392:Adipokines
chemical_list: D000178:Acrylamides; D001057:Apolipoproteins E; D016207:Cytokines; D000071838:Fibrillin-1; D000071837:Fibrillins; D005682:Gadolinium; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D019010:Vascular Cell Adhesion Molecule-1; D015091:beta-Alanine; C531963:2-(2,6-dichloro-4-((3-furan-2-ylacryloylamino)methyl)benzoylamino)-3-((thiazolidine-4-carbonyl)amino)propionic acid; C000605724:Fbn1 protein, mouse; D054392:Adipokines
keywords: blood–brain barrier; choroid plexus; fibrillin-1; xanthomas