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Sex-Dependent Molecular Mechanisms of Lipotoxic Injury in Brain Microvasculature: Implications for Dementia

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-...

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Autores principales: Nuthikattu, Saivageethi, Milenkovic, Dragan, Rutledge, John C., Villablanca, Amparo C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663125/
https://www.ncbi.nlm.nih.gov/pubmed/33142695
http://dx.doi.org/10.3390/ijms21218146
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author Nuthikattu, Saivageethi
Milenkovic, Dragan
Rutledge, John C.
Villablanca, Amparo C.
author_facet Nuthikattu, Saivageethi
Milenkovic, Dragan
Rutledge, John C.
Villablanca, Amparo C.
author_sort Nuthikattu, Saivageethi
collection PubMed
description 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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spelling pubmed-76631252020-11-14 Sex-Dependent Molecular Mechanisms of Lipotoxic Injury in Brain Microvasculature: Implications for Dementia Nuthikattu, Saivageethi Milenkovic, Dragan Rutledge, John C. Villablanca, Amparo C. Int J Mol Sci Article 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. MDPI 2020-10-31 /pmc/articles/PMC7663125/ /pubmed/33142695 http://dx.doi.org/10.3390/ijms21218146 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nuthikattu, Saivageethi
Milenkovic, Dragan
Rutledge, John C.
Villablanca, Amparo C.
Sex-Dependent Molecular Mechanisms of Lipotoxic Injury in Brain Microvasculature: Implications for Dementia
title Sex-Dependent Molecular Mechanisms of Lipotoxic Injury in Brain Microvasculature: Implications for Dementia
title_full Sex-Dependent Molecular Mechanisms of Lipotoxic Injury in Brain Microvasculature: Implications for Dementia
title_fullStr Sex-Dependent Molecular Mechanisms of Lipotoxic Injury in Brain Microvasculature: Implications for Dementia
title_full_unstemmed Sex-Dependent Molecular Mechanisms of Lipotoxic Injury in Brain Microvasculature: Implications for Dementia
title_short Sex-Dependent Molecular Mechanisms of Lipotoxic Injury in Brain Microvasculature: Implications for Dementia
title_sort sex-dependent molecular mechanisms of lipotoxic injury in brain microvasculature: implications for dementia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663125/
https://www.ncbi.nlm.nih.gov/pubmed/33142695
http://dx.doi.org/10.3390/ijms21218146
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