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The Effects of Gene-Environment Interactions Between Cadmium Exposure and Apolipoprotein E4 on Memory in a Mouse Model of Alzheimer's Disease

The Effects of Gene-Environment Interactions Between Cadmium Exposure and Apolipoprotein E4 on Memory in a Mouse Model of Alzheimer's Disease

Liang Zhang et al. Toxicol Sci.

Abstract

Cadmium (Cd) is a heavy metal of great public health concern. Recent studies suggested a link between Cd exposure and cognitive decline in humans. The ε4 allele, compared to the common ε3 allele, of the human apolipoprotein E gene (ApoE) is associated with accelerated cognitive decline and increased risks for Alzheimer's disease. To investigate the gene-environment interactions (GxE) between ApoE-ε4 and Cd exposure on cognition, we used a mouse model of Alzheimer's disease that expresses human ApoE-ε3 (ApoE3-KI (knock-in)) or ApoE-ε4 (ApoE4-KI). Mice were exposed to 0.6 mg/L CdCl2 through drinking water for 14 weeks, and assessed for hippocampus-dependent memory. A separate cohort was sacrificed immediately after exposure and used for Cd measurements and immunostaining. The peak blood Cd was 0.3-0.4 µg/L, within levels found in the US general population. All Cd-treated animals exhibited spatial working memory deficits in the novel object location (NOL) test. This deficit manifested earlier in ApoE4-KI mice than in ApoE3-KI within the same sex, and earlier in males than females within the same genotype. ApoE4-KI but not ApoE3-KI mice exhibited reduced spontaneous alternation later in life in the T-maze test. Finally, Cd exposure impaired neuronal differentiation of adult-born neurons in the hippocampus of male ApoE4-KI mice. These data suggest that a GxE between ApoE4 and Cd exposure leads to accelerated cognitive impairment and that impaired adult hippocampal neurogenesis may be one of the underlying mechanisms. Furthermore, male mice were more susceptible than female mice to this GxE effect when animals were young.

Keywords: ApoE; cadmium; cognition; neurotoxicity.

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