Abstract
The human Apolipoprotein E4 (ApoE4) variant is the strongest known genetic risk factor for Alzheimer’s disease (AD). Cadmium (Cd) has been shown to impair learning and memory at a greater extent in humanized ApoE4 knock-in (ApoE4-KI) mice as compared to ApoE3 (common allele)-KI mice. Here, we determined how cadmium interacts with ApoE4 gene variants to modify the gut-liver axis. Large intestinal content bacterial 16S rDNA sequencing, serum lipid metabolomics, and hepatic transcriptomics were analyzed in ApoE3- and ApoE4-KI mice orally exposed to vehicle, a low dose, or a high dose of Cd in drinking water. ApoE4-KI males had the most prominent changes in their gut microbiota, as well as a predicted down-regulation of many essential microbial pathways involved in nutrient and energy homeostasis. In the host liver, cadmium-exposed ApoE4-KI males had the most differentially regulated pathways; specifically, there was enrichment in several pathways involved in platelet activation and drug metabolism. In conclusion, Cd exposure profoundly modified the gut-liver axis in the most susceptible mouse strain to neurological damage namely the ApoE4-KI males, evidenced by an increase in microbial AD biomarkers, reduction in energy supply-related pathways in gut and blood, and an increase in hepatic pathways involved in inflammation and xenobiotic biotransformation.
Highlights
The human Apolipoprotein E4 (ApoE4) variant is the strongest known genetic risk factor for Alzheimer’s disease (AD)
Through 14-weeks of Cd exposure via drinking water at a concentration (0.6 mg/L per day) that resulted in a blood Cd concentration relevant to the general human blood Cd concentrations, it was shown that ApoE4 knock-in (ApoE4-knock in (KI)) mice had greater deficits in cognitive function and decreased adult hippocampal neurogenesis compared to ApoE3-KI mice
A previous study demonstrated that oral Cd exposure in drinking water increased the susceptibility of ApoE4-KI male mice to learning and memory deficits[5]
Summary
The human Apolipoprotein E4 (ApoE4) variant is the strongest known genetic risk factor for Alzheimer’s disease (AD). We determined how cadmium interacts with ApoE4 gene variants to modify the gut-liver axis. Cadmium-exposed ApoE4-KI males had the most differentially regulated pathways; there was enrichment in several pathways involved in platelet activation and drug metabolism. Cd exposure profoundly modified the gut-liver axis in the most susceptible mouse strain to neurological damage namely the ApoE4-KI males, evidenced by an increase in microbial AD biomarkers, reduction in energy supply-related pathways in gut and blood, and an increase in hepatic pathways involved in inflammation and xenobiotic biotransformation. This study provided direct evidence that ApoE4-KI mice (and especially males) are more vulnerable to the toxic effects of Cd. The gut-brain axis has been established as an important communication pathway between the central nervous system (CNS) and the gut microbiome[6]. Cytochrome P450s, an important family of Phase I oxidation enzymes, are responsible for the metabolism of almost
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