Student Research: Anna Engstrom

Gene-environment interaction between adult lead exposure and Apolipoprotein E4 on adult hippocampal neurogensis and cognitive behavior in mice
Toxicology (Tox)
Faculty Advisor: 


Alzheimer’s disease (AD) is characterized by progressive cognitive decline and memory loss. It has been hypothesized that environmental factors and gene-environment interactions (GXE) may increase AD risk and accelerate cognitive decline.  However, there is currently little direct evidence supporting this hypothesis. Interestingly, the E4 allele of the Apolipoprotein E gene (ApoE4) is the strongest known genetic risk factor for late-onset, sporadic AD, and it is also associated with accelerated cognitive decline compared to ApoE4 non-carriers. Furthermore, the heavy metal lead is a neurotoxicant of major public health importance and is associated with persistent cognitive and behavior deficits in humans. Using transgenic knock-in (KI) mice that express the human ApoE4 allele (ApoE4-KI), I found that adult-only lead exposure is sufficient to impair cognitive behavior and that lead-exposed ApoE4-KI mice develop more severe or exhibit earlier deficits in learning and memory compared to ApoE3-KI mice. Furthermore, these impairments in cognitive behavior are persistent and can occur long after the cessation of the lead exposure. I also found that females may be more sensitive to the effects of lead than males.

          Through a process called adult hippocampal neurogenesis, adult neural precursor cells in the dentate gyrus of the hippocampus continuously generate neurons throughout adulthood. These adult-born neurons contribute to hippocampus-dependent learning and memory. Importantly, the hippocampus is one of the earliest affected brain regions in AD patients, and the perturbation of adult hippocampal neurogenesis may cause deficits in hippocampus-dependent learning and memory, accelerate cognitive decline, and contribute to AD pathogenesis. While various factors have been shown to modulate adult neurogenesis, little is known about the effects of neurotoxicants or GXE on adult neurogenesis. Using an in vitro model of adult neurogenesis, I found that lead significantly increases apoptosis, inhibits proliferation, and impairs the spontaneous neuronal differentiation and maturation of adult neural precursor cells. Furthermore, I found that activation of the JNK and MAPK signaling pathways are important for lead cytotoxicity. I also utilized a transgenic knock-in mouse model of human ApoE4 carriers in order to assess for a GXE between lead and ApoE4 on adult hippocampal neurogenesis and found that adult lead exposure is sufficient to impair adult-born cell proliferation in vivo. I also observed more significant effects on adult-born neuron maturation in lead-treated ApoE4-KI females, suggesting that a GXE between lead and ApoE4 may significantly reduce the total number of adult-born neurons as well as perturb the maturation and dendritic complexity of adult-born neurons in the dentate gyrus of the hippocampus.

          Together, these data suggest that lead can directly act on adult neural stem cells to impair critical processes in adult hippocampal neurogenesis, which may contribute to its neurotoxicity and adverse effects on cognition in adults. My characterization of cognitive behavior and neurogenesis in lead-exposed ApoE4-KI mice also provides strong evidence of a GXE between ApoE4 and lead on cognitive impairment and adult hippocampal neurogenesis and may help elucidate the role of GXE and sex differences on AD risk.