Fibrillin-1 impairment enhances blood–brain barrier permeability and xanthoma formation in brains of apolipoprotein E-deficient mice. (4th June 2015)

• Record Type: Journal Article
• Authors: Van der Donckt, C.; Roth, L.; Vanhoutte, G.; Blockx, I.; Bink, D.I.; Ritz, K.; Pintelon, I.; Timmermans, J.-P.; Bauters, D.; Martinet, W.; Daemen, M.J.; Verhoye, M.; De Meyer, G.R.Y.
• Is Part Of: Neuroscience. Volume 295(2015)
• Page Start: 11
• Page End: 22
• Publication Date: 2015-06-04
• Subjects: ApoE apolipoprotein E -- ApoE−/− ApoE deficiency -- BBB blood–brain barrier -- BCSFB blood–cerebrospinal fluid barrier -- CSF cerebrospinal fluid -- ECM extracellular matrix -- Gd gadolinium -- IL-1β interleukin-1 beta -- MMP matrix metalloproteinases -- MRI magnetic resonance imaging -- ND normal diet -- PFA paraformaldehyde -- TEM transmission electron microcopy -- TJ tight junction -- TNF-α tumor necrosis factor-alpha -- TTC 2, 3, 5-triphenyltetrazolium chloride -- WD Western-type diet; xanthomas -- fibrillin-1 -- blood–brain barrier -- choroid plexus; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2015.03.023
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Dysfunctional fibrillin-1 impairs blood–brain barrier integrity. Peripheral leukocyte infiltration further degrades the blood–brain barrier. Accordingly, lipoproteins can enter the brain, resulting in xanthoma formation. 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.