Abstract
The Western diet (WD) and hyperlipidemia are risk factors for vascular disease, dementia, and cognitive impairment. However, the molecular mechanisms are poorly understood. This pilot study investigated the genomic pathways by which the WD and hyperlipidemia regulate gene expression in brain microvessels. Five-week-old C57BL/6J wild type (WT) control and low-density lipoprotein receptor deficient (LDL-R−/−) male mice were fed the WD for eight weeks. Differential gene expression, gene networks and pathways, transcription factors, and non-protein coding RNAs were evaluated by a genome-wide microarray and bioinformatics analysis of laser-captured hippocampal microvessels. The WD resulted in the differential expression of 1972 genes. Much of the differentially expressed gene (DEG) was attributable to the differential regulation of cell signaling proteins and their transcription factors, approximately 4% was attributable to the differential expression of miRNAs, and 10% was due to other non-protein coding RNAs, primarily long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs) not previously described to be modified by the WD. Lipotoxic injury resulted in complex and multilevel molecular regulation of the hippocampal microvasculature involving transcriptional and post-transcriptional regulation and may provide a molecular basis for a better understanding of hyperlipidemia-associated dementia risk.
Highlights
Alzheimer’s disease (AD) is a progressive disease characterized by a decline in cognitive function and loss of memory, and its etiology includes both environmental and genetic factors [1]
Our study focused on the molecular mechanisms of differential gene expression in the brain microvessels due to their significance in the pathogenesis of vascular dementia, and due to our recently published work demonstrating that the Western diet (WD) results in increased blood–brain barrier (BBB) permeability and cognitive impairment [7], providing a functional correlation to the molecular pathways indicated in this experimental study
This is of significance because a disruption of endothelial permeability in the brain, where endothelial cells are part of a neurovascular unit, results in BBB dysfunction which may be a significant contributor to the pathogenesis of cognitive impairment, amyotrophic lateral sclerosis, or Alzheimer’s disease [37]
Summary
Alzheimer’s disease (AD) is a progressive disease characterized by a decline in cognitive function and loss of memory, and its etiology includes both environmental and genetic factors [1]. The strongest genetic risk factor for AD is the ε4 variant of apolipoprotein E (ApoE), yet the most common cause of vascular dementia (VaD) is cerebral small vessel disease [2]. Risk factors for cardiovascular disease (CVD) are known to overlap with risk factors of AD and VaD [1], still the mechanistic links have not been clearly established [3]. As a result, understanding the effect of CVD risk factors in dementia provides potential important therapeutic targets for the prevention of cognitive dysfunction. The global increase in obesity has been linked to a decline in complex carbohydrate and fiber intake, diets with fewer fruits and vegetables, and a shift towards diets high in fat and refined sugars—otherwise known as the Western-type diet (WD). A greater risk of AD is correlated with high concentrations of low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) [5] and increased consumption of saturated
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