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Evidence in support of chromosomal sex influencing plasma based metabolome vs APOE genotype influencing brain metabolome profile in humanized APOE male and female mice
- Source :
- PLoS ONE, Vol 15, Iss 1, p e0225392 (2020), PLoS ONE
- Publication Year :
- 2020
- Publisher :
- Public Library of Science (PLoS), 2020.
-
Abstract
- Late onset Alzheimer's disease (LOAD) is a progressive neurodegenerative disease with four well-established risk factors: age, APOE4 genotype, female chromosomal sex, and maternal history of AD. Each risk factor impacts multiple systems, making LOAD a complex systems biology challenge. To investigate interactions between LOAD risk factors, we performed multiple scale analyses, including metabolomics, transcriptomics, brain magnetic resonance imaging (MRI), and beta-amyloid assessment, in 16 months old male and female mice with humanized human APOE3 (hAPOE3) or APOE4 (hAPOE4) genes. Metabolomic analyses indicated a sex difference in plasma profile whereas APOE genotype determined brain metabolic profile. Consistent with the brain metabolome, gene and pathway-based RNA-Seq analyses of the hippocampus indicated increased expression of fatty acid/lipid metabolism related genes and pathways in both hAPOE4 males and females. Further, female transcription of fatty acid and amino acids pathways were significantly different from males. MRI based imaging analyses indicated that in multiple white matter tracts, hAPOE4 males and females exhibited lower fractional anisotropy than their hAPOE3 counterparts, suggesting a lower level of white matter integrity in hAPOE4 mice. Consistent with the brain metabolomic and transcriptomic profile of hAPOE4 carriers, beta-amyloid generation was detectable in 16-month-old male and female brains. These data provide therapeutic targets based on chromosomal sex and APOE genotype. Collectively, these data provide a framework for developing precision medicine interventions during the prodromal phase of LOAD, when the potential to reverse, prevent and delay LOAD progression is greatest.
- Subjects :
- Male
0301 basic medicine
Apolipoprotein E
Aging
Apolipoprotein E4
Gene Expression
Physiology
Biochemistry
Transcriptome
Mice
Mathematical and Statistical Techniques
0302 clinical medicine
Glucose Metabolism
Genotype
Age of Onset
Principal Component Analysis
Sex Characteristics
Sex Chromosomes
Multidisciplinary
Statistics
Brain
Genomics
Lipids
Magnetic Resonance Imaging
3. Good health
medicine.anatomical_structure
Physical Sciences
Amino Acid Analysis
Metabolome
Carbohydrate Metabolism
Medicine
Female
Transcriptome Analysis
Research Article
Sex characteristics
Science
Mice, Transgenic
Biology
Research and Analysis Methods
White matter
03 medical and health sciences
Apolipoproteins E
Metabolomics
Alzheimer Disease
Genetics
medicine
Animals
Humans
Statistical Methods
Molecular Biology Techniques
Molecular Biology
Molecular Biology Assays and Analysis Techniques
Amyloid beta-Peptides
Biology and Life Sciences
Computational Biology
Genome Analysis
Lipid Metabolism
Amino Acid Metabolism
Disease Models, Animal
Metabolism
030104 developmental biology
Multivariate Analysis
Age of onset
Mathematics
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 15
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....a682cad6303172503e24650d4eec6e14