GXE and Cognitive Impairment

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Lead is a heavy metal of great public health concern in the US and globally. In addition to its well- characterized developmental neurotoxicity, cumulative lead exposure is also neurotoxic to adults and can lead to accelerated, persistent cognitive decline in adult humans. The apolipoprotein E gene (ApoE) exists as three polymorphic alleles in humans (ε2, ε3, ε4); the ApoE -ε3 allele (simplified as ApoE3 hereafter) is the most common allele. The ApoE-ε4 allele (simplified as ApoE4 hereafter) is associated with increased risk for Alzheimer’s disease, and accelerated cognitive decline even in the absence of Alzheimer’s disease pathology. The hippocampus is a region of the brain critical for learning and memory, especially spatial learning. Adult hippocampal neurogenesis is the process whereby adult neural stem cells in the dentate gyrus of the hippocampus leads to the generation and functional integration of adult-born neurons in the hippocampus. These adult-born neurons can influence hippocampus-dependent learning and memory. Although adult neurogenesis is modulated by various extracellular stimuli, by the environment, and by neurotoxicants including lead and ethanol, there is a paucity of information regarding the effect of gene-environment interactions (GxE) on adult neurogenesis. This proposal focuses on the effect of lead-genetic background interactions on adult neurogenesis and hippocampus-dependent learning and memory.