Cerebrovascular Pathology in Hypertriglyceridemic APOB-100 Transgenic Mice

Zsófia Hoyk; Melinda E Tóth; Nikolett Lénárt; Dóra Nagy; Brigitta Dukay; Alexandra Csefová; Ágnes Zvara; György Seprényi; András Kincses; Fruzsina R Walter; Szilvia Veszelka; Judit Vígh; Beáta Barabási; András Harazin; Ágnes Kittel; László G Puskás; Botond Penke; László Vígh; Mária A Deli; Miklós Sántha

doi:10.3389/fncel.2018.00380

Cerebrovascular Pathology in Hypertriglyceridemic APOB-100 Transgenic Mice

Front Cell Neurosci. 2018 Oct 25:12:380. doi: 10.3389/fncel.2018.00380. eCollection 2018.

Authors

Zsófia Hoyk¹, Melinda E Tóth², Nikolett Lénárt², Dóra Nagy², Brigitta Dukay², Alexandra Csefová², Ágnes Zvara³, György Seprényi⁴, András Kincses¹, Fruzsina R Walter¹, Szilvia Veszelka¹, Judit Vígh¹, Beáta Barabási¹, András Harazin¹, Ágnes Kittel⁵, László G Puskás³, Botond Penke⁶, László Vígh², Mária A Deli¹, Miklós Sántha²

Affiliations

¹ Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
² Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
³ Laboratory of Functional Genomics, Core Facilities, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
⁴ Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
⁵ Laboratory of Molecular Pharmacology, Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
⁶ Department of Medical Chemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary.

Abstract

Hypertriglyceridemia is not only a serious risk factor in the development of cardiovascular diseases, but it is linked to neurodegeneration, too. Previously, we generated transgenic mice overexpressing the human APOB-100 protein, a mouse model of human atherosclerosis. In this model we observed high plasma levels of triglycerides, oxidative stress, tau hyperphosphorylation, synaptic dysfunction, cognitive impairment, increased neural apoptosis and neurodegeneration. Neurovascular dysfunction is recognized as a key factor in the development of neurodegenerative diseases, but the cellular and molecular events linking cerebrovascular pathology and neurodegeneration are not fully understood. Our aim was to study cerebrovascular changes in APOB-100 transgenic mice. We described the kinetics of the development of chronic hypertriglyceridemia in the transgenic animals. Increased blood-brain barrier permeability was found in the hippocampus of APOB-100 transgenic mice which was accompanied by structural changes. Using transmission electron microscopy, we detected changes in the brain capillary endothelial tight junction structure and edematous swelling of astrocyte endfeet. In brain microvessels isolated from APOB-100 transgenic animals increased Lox-1, Aqp4, and decreased Meox-2, Mfsd2a, Abcb1a, Lrp2, Glut-1, Nos2, Nos3, Vim, and in transgenic brains reduced Cdh2 and Gfap-σ gene expressions were measured using quantitative real-time PCR. We confirmed the decreased P-glycoprotein (ABCB1) and vimentin expression related to the neurovascular unit by immunostaining in transgenic brain sections using confocal microscopy. We conclude that in chronic hypertriglyceridemic APOB-100 transgenic mice both functional and morphological cerebrovascular pathology can be observed, and this animal model could be a useful tool to study the link between cerebrovascular pathology and neurodegeneration.

Keywords: P-glycoprotein; apolipoprotein B-100; astroglia; blood-brain barrier; brain endothelial cell; cerebrovascular pathology; hypertriglyceridemia; tight junction.