Neurotoxicity of particulate matter and its interaction with APOE in neurodegeneration

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是老年痴呆症最常见的病因， 美国以及其他许多国家的健康挑战。尽管有大量的研究工作， 虽然AD的发病机制和发病机制存在差异，但迟发性、散发性AD的确切病因仍然难以捉摸。虽然遗传倾向 包括来自人类遗传学研究的已知风险基因在发病机制中起着重要作用， AD的病因学，最近越来越多的证据强烈表明，环境因素的作用正在显现， 贡献，特别是空气污染的有毒成分，包括但不限于颗粒物（PM） 和金属，对AD的进展和发病的影响。因此，研究空气污染如何驱动 神经退行性变和AD风险基因是否调节其神经毒性和神经元死亡，作为一个经验性的 基因x环境（GxE）相互作用的例子，以支持AD的机制为基础的病因。作为 越来越多的人类和动物模型研究证实了目前已知的 风险基因和暴露于空气污染，单独或组合，在AD神经病理学和 神经变性，我们仍然专注于确定环境PM的关键神经毒性机制， 在环境空气中发现大量有毒成分，随后导致加速 神经变性和AD的临床发作。本研究的总体目标是：1） 在一种新的小鼠模型中，综合评价大气PM的神经毒性及其环境风险。 2）确定决定对AD的敏感性或恢复力的关键基因和机制， PM引起的神经元死亡。在这个应用程序中，我们包括几个创新的工具，如一个新颖的鼠标 模型，人类iPSC衍生的神经元和基于CRISPR的功能基因组学，以仔细评估 PM的神经毒性，其发展和加重AD表型的风险，以及GxE相互作用，所有这些 与现有研究结果相比，其可能更具临床相关性，并适用于更广泛的一般人群 来自广泛使用的过表达家族性AD突变的动物模型。据我们所知，在体内和 体外模型是模拟和评估环境对迟发性癫痫的影响的最佳模型 人类AD因此，本研究的结果对理解 迟发性AD的神经退行性机制和GxE病因。最后，这个建议是可行的，高度- 对于在GxE背景下评价AD的病因和进展具有重要意义和高度相关性 交互.我们认为，这些成果可以对实地产生重大影响，同时加快进展 了解环境对AD发病机制的影响。

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common cause of dementia among elderly and is an apparent public health challenge in the U.S. as well as many other countries. Despite the extensive research effort on all aspects of AD, the exact causes of late-onset, sporadic AD remain elusive. Although genetic predispositions including known risk genes from human genetics studies are playing a prominent role in the pathogenesis and etiology of AD, recent growing bodies of evidence strongly suggest an emerging role of environmental contribution, particularly toxic constituents of air pollution including, but not limited to, particulate matter (PM) and metals, to the progression and onset of AD. Thus, it is critical to investigate how air pollution drives neurodegeneration and whether AD risk genes modulate its neurotoxicity and neuronal death, as an empirical example of the gene x environment (GxE) interactions to support the mechanism-based etiology of AD. As increasing number of studies in humans and animal models have confirmed the pivotal role of currently known risk genes and exposure to air pollution, independently or in combination, in AD neuropathology and neurodegeneration, we stay focuses on determining key neurotoxic mechanisms of ambient PM, the most abundant toxic constituents found in the ambient air, which subsequently leads to accelerated neurodegeneration and the clinical onset of AD. The overarching objectives of this study are 1) to comprehensively evaluate neurotoxicity of ambient PM and its environmental risk in a novel mouse model of late-onset AD, and 2) to identify key genes and mechanisms that determine the sensitivity or resilience to neuronal death triggered by PM. In this application, we include several innovative tools, such as a novel mouse model, human iPSC-derived neurons and the CRISPR-based functional genomics, to carefully assess the neurotoxicity of PM, its risk for developing and exacerbating AD phenotypes, and the GxE interactions, all of which could be more clinically relevant and applied to broader general population compared to existing findings from widely used animal models overexpressing familial AD mutations. In our knowledge, proposed in vivo and in vitro models are the best suited models to simulate and evaluate the environmental contribution to late-onset AD in humans. Thus, outcomes from this study maintain high translational significances to understand neurodegenerative mechanisms and the GxE etiology of late-onset AD. Lastly, this proposal is feasible, highly- significant, and highly-relevant to evaluate the etiology and progression of AD in the context of the GxE interactions. We believe that the outcomes could have large impact to the field, while accelerating progress towards understanding the environmental impact on the pathogenesis of AD.