Cerebrovascular Pathology in Hypertriglyceridemic APOB-100 Transgenic Mice

Hoyk, Zsófia and Tóth, Erzsébet Melinda and Lénárt, Nikolett and Nagy, Dóra and Dukay, Brigitta and Csefová, Alexandra and Zvara, Ágnes and Seprényi, György and Kincses, András and Walter, Fruzsina and Veszelka, Szilvia and Vigh, Judit and Barabási, Beáta and Harazin, András and Kittel, Ágnes and Puskás, László and Penke, Botond and Vigh, László and Deli, Mária Anna and Sántha, Miklós (2018) Cerebrovascular Pathology in Hypertriglyceridemic APOB-100 Transgenic Mice. FRONTIERS IN CELLULAR NEUROSCIENCE, 12. No.-380. ISSN 1662-5102

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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.

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