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

Autoři: Yuan Shang aff001;  Aarti Mishra aff001;  Tian Wang aff001;  Yiwei Wang aff001;  Maunil Desai aff002;  Shuhua Chen aff001;  Zisu Mao aff001;  Loi Do aff003;  Adam S. Bernstein aff004;  Theodore P. Trouard aff003;  Roberta D. Brinton aff001
Působiště autorů: Center for Innovation in Brain Science, University of Arizona, Tucson, Arizona, United States of America aff001;  School of Pharmacy, University of Southern California, Los Angeles, California, United States of America aff002;  Biomedical Engineering, University of Arizona, Tucson, Arizona, United States of America aff003;  College of Medicine, University of Arizona, Tucson, Arizona, United States of America aff004
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0225392


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.

Klíčová slova:

Amino acid analysis – Amino acid metabolism – Gene expression – Glucose metabolism – Lipid metabolism – Metabolomics – principal component analysis – Transcriptome analysis


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