Mechanisms of gene-environment interaction in developmental lead exposure leading to Alzheimer's disease phenotypes

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Project Summary Developmental exposure to heavy metals, such as lead (Pb), causes systematic damage to the central nervous system and impairs many neurological targets. Some of these biological perturbations, such as altered synaptic plasticity and endosome trafficking, are shared with Alzheimer's Disease (AD). Epigenetic mechanisms, given potency and latency in gene regulation, offer a plausible route to relay impacts from early-life environmental exposure events to AD. The exact molecular mechanism, however, remains elusive. The goal of this proposal is to define the epigenetic mechanism contributing to altered synaptic plasticity arising from developmental Pb exposure addressing the contributions of gene-by-environment (GxE) interactions in accelerating the progression of AD. Our preliminary studies and prior literature suggest persistent alterations in synaptic plasticity, primarily arising from changes in glutamate receptors, including NMDAR and AMPAR. Alterations in endosomal trafficking are also heavily implied. We formulated our central hypothesis that developmental Pb exposure alters the transcription of glutamate receptors via epigenetic regulation affecting synaptic plasticity with the effects exacerbated when coupled with the AD genetic risk factor, SORL1. This GxE interaction compromises endosomal trafficking and glutamate receptor recycling, which eventually leads to the onset of an AD-like phenotype manifested by protein aggregation markers. We adopted a multiplex model including cortical neurons derived from human induced pluripotent stem cells (hiPSCs) and a zebrafish animal model with and without a known late-onset AD (LOAD) risk factor (SORL1). We designed our experiments to dissect contributions from environmental (E), genetic (G), and GxE driven events in altering synaptic plasticity and the manifestation of AD- like phenotypes. We will test our hypothesis in three aims. Aim 1 will elucidate the impact of developmental Pb exposure and SORL1 effects on neuron susceptibility of protein aggregates. Aim 2 will reveal the molecular origin conferring developmental Pb neurotoxicity to an AD-like phenotype. Aim 3 will define subcellular alterations in the post-synapse associated with an AD-like phenotype. Collectively, we will curate time-dependent information about molecular changes in the transcriptome and epigenome, along with alterations in ultrastructure of post-synaptic spine. We will use the aggregated information to infer causative relations among different events by assuming early events are likely to drive late ones. We expect that GxE interactions arising from developmental Pb exposure and SORL1 mutation to induce a phenotype closely resembling AD, followed by SORL1 mutation only, Pb exposure in wild type, and untreated wild type. Furthermore, we will reveal novel targets mediating the latent effects of developmental Pb exposure on neurodegeneration risks via mining of our dataset and verification of the efficacy of underlying epigenetic profiles of glutamate receptors in accelerating AD onset and progression risks. The knowledge generated will enlighten the molecular mechanism of Pb neurotoxcity and connections of early life Pb exposure to AD progression addressing goals of PAR-22-048.