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.