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Publication
Sex-Dependent Molecular Mechanisms of Lipotoxic Injury in Brain
Microvasculature: Implications for Dementia.
Authors Nuthikattu S, Milenkovic D, Rutledge JC, Villablanca AC
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal International journal of molecular sciences
Year 2020
Date Published 10/1/2020
Volume : Pages 21 : Not Specified
PubMed Reference 33142695
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.




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