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.
Highlights
There is growing preclinical and clinical evidence that pathological changes at the level of the neurovascular unit (NVU), comprising all the cell types of cerebral microvessels and the surrounding neural tissue, lead to secondary neuronal injury and neurodegenerative diseases, including Alzheimer’s disease (AD) (Zhao et al, 2015)
A statistically significant difference was detected in transgenic compared to wild-type animals at every time point (7, 9, and 12-month, n = 5 animals/group) indicating chronic hypertriglyceridemia in APOB-100 transgenic mice (Figure 1A)
We measured a significant increase in the blood-brain barrier (BBB) permeability (p < 0.05) for the small molecular weight marker SF in the hippocampal region of transgenic mice, while alteration in the extravasation of the large serum protein albumin showed a non-significant trend (Figure 1B)
Summary
There is growing preclinical and clinical evidence that pathological changes at the level of the neurovascular unit (NVU), comprising all the cell types of cerebral microvessels and the surrounding neural tissue, lead to secondary neuronal injury and neurodegenerative diseases, including Alzheimer’s disease (AD) (Zhao et al, 2015). Several families of active influx and efflux transporters and transcytotic receptor systems regulate the exchange of small and large nutrients and metabolites across the BBB (Zlokovic, 2008) Both the structure and functions of the BBB are damaged in AD: the barrier function of TJs is impaired, the energy supply of neural cells is decreased, the entry of neurotoxic agents is elevated and the clearance of Aβ peptides is reduced (Zlokovic, 2008, 2011; Lyros et al, 2014; Di Marco et al, 2015; Zhao et al, 2015). NVU and BBB pathologies have been increasingly investigated in genetic and other animal models of AD (Nicolakakis and Hamel, 2011), but there are very few models focusing on the link between atherosclerosis and dementia (Li et al, 2003; Lane-Donovan et al, 2016) or NVU changes
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