Abstract
Cardiovascular risk factors and biologic sex play a role in vascular dementia which is characterized by progressive reduction in cognitive function and memory. Yet, we lack understanding about the role sex plays in the molecular mechanisms whereby lipid stress contributes to cognitive decline. Five-week-old low-density lipoprotein deficient (LDL-R −/−) male and female mice and C57BL/6J wild types (WT) were fed a control or Western Diet for 8 weeks. Differential expression of protein coding and non-protein coding genes (DEG) were determined in laser captured hippocampal microvessels using genome-wide microarray, followed by bioinformatic analysis of gene networks, pathways, transcription factors and sex/gender-based analysis (SGBA). Cognitive function was assessed by Y-maze. Bioinformatic analysis revealed more DEGs in females (2412) compared to males (1972). Hierarchical clusters revealed distinctly different sex-specific gene expression profiles irrespective of diet and genotype. There were also fewer and different biologic responses in males compared to females, as well as different cellular pathways and gene networks (favoring greater neuroprotection in females), together with sex-specific transcription factors and non-protein coding RNAs. Hyperlipidemic stress also resulted in less severe cognitive dysfunction in females. This sex-specific pattern of differential hippocampal microvascular RNA expression might provide therapeutic targets for dementia in males and females.
Highlights
Alzheimer’s disease (AD) is the most widespread neurodegenerative disease [1], the most common form of dementia, and has no known cure [2]
We have previously shown in Apolipoprotein (ApoE)-deficient male mice that the western diet (WD) leads to Activating transcription factor 3 (ATF3)-mediated pro-apoptotic, inflammatory, and oxidative stress related neurovascular inflammation in brain microvessels, shedding light on one operative molecular mechanism [15]
Mean weight of Low density lipoprotein receptor (LDL-R) −/− female mice at baseline was 14 g and increased by an average of 36% when fed the control diet (CD) and 68% when fed with WD
Summary
Alzheimer’s disease (AD) is the most widespread neurodegenerative disease [1], the most common form of dementia, and has no known cure [2]. 50 million people around the world are currently living with dementia [3]. By 2050, the number of AD cases is projected to increase to 14 million Americans [6]. Among the 5.8 million Americans with AD, two thirds are women [7] and women have a later onset but more rapid cognitive decline after a diagnosis of dementia than men [8]. These differences do not appear to be solely explainable by the longer life expectancy of women when compared to men
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