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

项目摘要 发育中接触重金属，如铅(铅)，会对中枢神经系统造成系统性损害 神经系统，并损害许多神经靶点。其中一些生物扰动，如改变 突触可塑性和内小体运输是阿尔茨海默病(AD)的共同特征。表观遗传机制， 考虑到基因调控的效力和潜伏期，提供了一条合理的途径来传递来自早期生命环境的影响 暴露于AD的事件。然而，确切的分子机制仍然难以捉摸。这项提议的目标是 明确发育铅引起突触可塑性改变的表观遗传学机制 暴露于基因与环境(GxE)相互作用在加速 AD的进展。我们的初步研究和先前的文献表明，突触可塑性持续变化， 主要是由于谷氨酸受体的变化，包括NMDAR和AMPAR。内涵体的改变 人口贩运也在很大程度上隐含着。我们提出了我们的核心假设，即发育中的铅暴露会改变 谷氨酸受体转录通过表观遗传调控影响突触可塑性及其作用 当与阿尔茨海默病遗传风险因素SORL1结合时，病情会加剧。这种GxE交互影响了 内体转运和谷氨酸受体循环，最终导致AD样发作 蛋白质聚集标记所表现的表型。我们采用了包括大脑皮层神经元在内的多重模型。 来源于人诱导多能干细胞(HiPSCs)和斑马鱼动物模型 已知的晚发性AD(负荷)危险因素(SORL1)。我们设计我们的实验是为了从 环境(E)、遗传(G)和GxE驱动事件在改变突触可塑性和AD表现中的作用 就像表型一样。我们将从三个方面检验我们的假设。目标1将阐明发育性铅的影响 暴露和SORL1对蛋白质聚集体神经元敏感性的影响。目标2将揭示分子 发育中铅对AD样表型的神经毒性的来源。目标3将定义亚细胞变化 在与AD样表型相关的突触后。总体而言，我们将策划依赖时间的 转录组和表观基因组中的分子变化以及超微结构的变化 突触后脊椎。我们将使用汇总的信息来推断不同事件之间的因果关系 通过假设早期的事件可能会推动后期的事件。我们预计GxE互动源于 发育期铅暴露和SORL1突变诱导出与AD非常相似的表型，随后是 仅SORL1突变，野生型和未经处理的野生型铅暴露。此外，我们将揭开小说的面纱 通过挖掘OUR基因介导发育性铅暴露对神经退行性变风险潜在影响的靶点 谷氨酸受体潜在表观遗传图谱加速作用的数据集和验证 AD的发病和进展风险。所产生的知识将启迪铅的分子机制 神经毒性和早期生命铅暴露与AD进展的联系解决了PAR-22-048的目标。

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.