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

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.

Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice

“…Emerging evidence indeed points to a distinct impact of APOE genotype on brain lipid metabolism [76,87] with a sex bias [93]. In the latter study, lipid clustering by principal component analysis of cortical lipidomes unravels sample segregation by sex in APOE3 but not in APOE4 16 month-old mice [93]. That is, sex differences were observed in APOE3 but not in APOE4 mice, as in our study.…”

“…That is, sex differences were observed in APOE3 but not in APOE4 mice, as in our study. Specifically, there was a trend for greater concentrations of phosphatidylcholines and lysophosphatidylcholines in APOE3 male than in APOE3 female mice [93]. Taking together these and our results, it is plausible that the interplay of sex, APOE genotype and age differently shapes the composition of lipid milieus in male and females through life, resulting in distinct astrocytic Ca 2+ responses.…”

“…Note that ex-vivo Ca 2+ responses in female mice resemble Ca 2+ responses in immortalized astrocytes in the absence of lipoproteins. Emerging evidence indeed points to a distinct impact of APOE genotype on brain lipid metabolism [76,87] with a sex bias [93]. In the latter study, lipid clustering by principal component analysis of cortical lipidomes unravels sample segregation by sex in APOE3 but not in APOE4 16 month-old mice [93].…”

Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders

“…As ketone bodies are primarily derived from white matter, white matter volume, myelinated fiber volume and myelin sheath volume were all reduced in aged female APP/PS1 double-transgenic mice compared to males ( Zhou et al, 2018 ). A recent metabolomic and transcriptomic study in APOE -TR mice confirmed that metabolic shifts in the female ε4 brain are accompanied by loss of myelin integrity ( Shang et al, 2020 ).…”

Sex Differences in Alzheimer’s Disease: Insights From the Multiomics Landscape

“…Many more transcription factors differentially expressed in APOE4 + females versus APOE3 + females than those in APOE4 + males versus APOE3 + males, with PSEN2 expressed highest in the temporal cortex of APOE4 + females and CNTNAP2 in APOE4 + males (91). A separate study performed transcriptomic and J o u r n a l P r e -p r o o f metabolomic analyses of 16 months old human APOE mice (92). There were more DEGs between sexes identified with APOE4 genotype when compared to APOE3 genotype.…”