Evidence in support of chromosomal sex influencing plasma based metabolome vs APOE genotype influencing brain metabolome profile in humanized APOE male and female mice

• DOI: 10.1371/journal.pone.0225392
• Publication Date: 2020-01-09T18:30:39Z
• Authors: Yuan Shang; Aarti Mishra; Tian Wang; Yiwei Wang; Maunil Desai; Shuhua Chen; Zisu Mao; Loi Do; Adam S. Bernstein; Theodore P. Trouard; Roberta D. Brinton
• Keywords: Metabolome; Apolipoprotein E; Humanized mouse

Late onset Alzheimer's disease (LOAD) is a progressive neurodegenerative with four well-established risk factors: age, APOE4 genotype, female chromosomal sex, and maternal history of AD. Each factor impacts multiple systems, making LOAD complex systems biology challenge. To investigate interactions between factors, we performed scale analyses, including metabolomics, transcriptomics, brain magnetic resonance imaging (MRI), beta-amyloid assessment, in 16 months old male mice humanized human APOE3 (hAPOE3) or (hAPOE4) genes. Metabolomic analyses indicated sex difference plasma profile whereas APOE genotype determined metabolic profile. Consistent the metabolome, gene pathway-based RNA-Seq hippocampus increased expression fatty acid/lipid metabolism related genes pathways both hAPOE4 males females. Further, transcription acid amino acids were significantly different from males. MRI based that white matter tracts, females exhibited lower fractional anisotropy than their hAPOE3 counterparts, suggesting level integrity mice. metabolomic transcriptomic carriers, generation was detectable 16-month-old brains. These data provide therapeutic targets on genotype. Collectively, these framework for developing precision medicine interventions during prodromal phase LOAD, when potential to reverse, prevent delay progression greatest.