Cellular and molecular mechanisms of cadmium neurotoxicity and cadmium interaction with APOE4 on memory impairment

Abstract

Cadmium (Cd) is a ubiquitous toxic heavy metal and an emerging neurotoxicant. While Cd neurotoxicity is increasingly documented in epidemiology and toxicology studies at levels relevant to the general US population, the underlying mechanisms are not yet well understood. This dissertation describes two studies that aim to elucidate the cellular and molecular mechanisms of Cd neurotoxicity impairments of hippocampus-dependent memory.Cd has the ability to mimic calcium ions (Ca2+) and interfere with intracellular Ca2+ levels, Ca2+ binding activity, and Ca2+ signaling. However, little is known about Cd’s effects on Ca2+ activity in neurons at low level exposures. In the first study, in vivo imaging of neuronal Ca2+ activity in freely behaving mice demonstrated that exposure to environmentally relevant levels of Cd inhibits calcium activity. Environmental factors such as Cd exposure and gene-environment interactions (GxE) may increase Alzheimer’s disease (AD) and accelerate cognitive decline. Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset AD associated with accelerated cognitive decline in carriers of E4 alleles. Our laboratory has found correlative evidence suggesting that impairment of adult neurogenesis, a process of generation of functional new neurons through adulthood with implications on hippocampus function, may be a key mechanism underlying Cd-induced impairment of hippocampus-dependent memory. The second study utilized an inducible Cre-lox recombination transgenic mouse line that genetically and conditionally stimulate adult neurogenesis with humanized ApoE4 knock-in (ApoE4-KI) background. Our results demonstrate that stimulation of adult neurogenesis after Cd exposure rescued mice from Cd-induced impairments of hippocampus-dependent memory. The studies described in this dissertation are the first to describe Cd effects on brain Ca2+ activity in vivo in freely behaving mice and provide strong evidence for a causal link between adult neurogenesis and memory impairment in a GxE model of ApoE4 and Cd, respectively. Together, these studies describe cellular and molecular mechanisms underlying Cd neurotoxicity at exposure levels relevant to the general population.