Impact of Toxic Metal Exposures in Novel Genetic Mouse Models of Late-Onset Alzheimer's Disease

迟发性阿尔茨海默病(LOAD)是痴呆症的主要原因，也是发病率的主要贡献者， 死亡率和医疗成本。LOAD脑病理的主要特征是与年龄相关的堆积 由淀粉样蛋白(Aβ，Aβ)斑块和神经原纤维缠结(过度磷酸化的tau蛋白)组成。遗传易感性 因素(如载脂蛋白E4)有助于负荷病理和表型，但只占负荷风险的30%-70%。 研究表明，负荷的复杂性和异质性，以及个人风险和健康结果，是 受遗传和环境因素相互作用的影响，如高脂肪饮食，久坐行为， 和生命暴露于环境毒物，包括铅(铅)、镉(镉)和砷(砷)。 铅、镉和砷的暴露很常见，特别是在弱势群体(城市、农村)，引起了关注 关于负荷风险差异、社会经济/种族不平等和环境正义。而铅、镉和砷 神经毒素与已知的负荷相关，这些环境中的分子机制 毒物介导基因-曝光组相互作用和调节负载病理生物学是未知的，并且可能是 可修改的。该项目将使用由NIA资助的AD模型创建的创新的新鼠标模型 与人类相关表型的联盟(MODEL-AD，U54-AG054345)调查慢性 暴露于三种普遍存在的环境神经毒物(铅、镉、砷)会影响大脑老化和负荷风险。这 该项目响应了NIA的一项新倡议(“AD/ADRD治疗的精确环境健康方法 和风险预防“)，以支持临床前研究以调节基因-环境的机制为目标 毒物暴露对AD/ADRD发病机制的影响和利用NIA资助的AD/ADRD 资源(波士顿大学ADRC，P30-AG072978；生物金属组学中心；模型-AD小鼠模型， 系统生物学分析，杰克逊实验室)。我们将检验我们的假设，即长期接触铅、镉或 在饮用水中：(I)诱导有毒金属/类金属在大脑中积累，(Ii)调节与负荷相关的 病理/表型(ATN：Aβ，tau蛋白病，神经变性，认知障碍；血脑屏障， 微血管功能障碍、神经炎症、脑生物金属(铜、锌、铁)代谢紊乱)；以及(Iii)相互作用 与LOAD相关的多基因变异。在目标1中，我们将调查早年/中年接触铅的影响， CD，关于AD/ADRD的病理、表型和生物标记物在新的创新的LOAD3小鼠模型(三重)中 人源化Aβ(hAβ)、MAPT(HTau)、hAPOE4纯合。在目标2中，我们将识别与负荷相关的基因， 蛋白质组网络，以及受铅、镉、砷暴露调控的分子通路(每一目标1)。在目标3中，我们 研究特定的负荷遗传风险因素(ABCA7、PLCG2、MTHFR的变异)，这些数据表明 与毒物代谢不同地相互作用，以调节负荷风险。结果将确定通过哪些机制 常见的金属/金属类神经毒物暴露会增加AD/ADRD的风险，并优先考虑新的治疗策略 降低风险，预防疾病，减轻毒物，并对负荷和ADRDS进行治疗干预。

Late-onset Alzheimer’s disease (LOAD) is the leading cause of dementia and a major contributor to morbidity, mortality, and healthcare costs. Cardinal hallmarks of LOAD brain pathology include age-related accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (hyperphosphorylated tau protein). Genetic susceptibility factors (e.g., ApoE4) contribute to LOAD pathology and phenotype but account for only 30-70% of LOAD risk. Research indicates that LOAD complexity and heterogeneity, as well as individual risk and health outcomes, are modulated by interactions between genetics and environmental factors such as high-fat diet, sedentary behavior, and life exposure (“exposome”) to environmental toxicants, including lead (Pb), cadmium (Cd), and arsenic (As). Pb, Cd, and As exposure is common, especially in disadvantaged populations (urban, rural), raising concern about LOAD risk disparities, socioeconomic/racial inequities, and environmental justice. While Pb, Cd, and As are neurotoxins with known LOAD association, the molecular mechanisms by which these environmental toxicants mediate gene-exposome interactions and modulate LOAD pathobiology are unknown and potentially modifiable. This project will use innovative new mouse models created by the NIA-funded MODEL-AD Consortium (MODEL-AD, U54-AG054345) with human-relevant phenotyping to investigate how chronic exposure to three ubiquitous environmental neurotoxicants (Pb, Cd, As) affect brain aging and LOAD risk. This project is responsive to a new NIA initiative (“Precision Environmental Health Approach to AD/ADRD Treatment and Risk Prevention”) to support preclinical research targeting mechanisms that mediate gene-environmental toxicant exposure effects (“exposome”) on AD/ADRD pathogenesis and leverages NIA-funded AD/ADRD resources (Boston University ADRC, P30-AG072978; Center for Biometallomics; MODEL-AD mouse models, systems biology analytics, Jackson Laboratory). We will test our hypothesis that chronic exposure to Pb, Cd, or As in drinking water: (i) induces accumulation of toxic metal/metalloid in brain, (ii) modulates LOAD-relevant pathologies/phenotypes (ATN: Aβ, tau proteinopathy, neurodegeneration, cognitive deficits; blood-brain barrier, microvascular dysfunction, neuroinflammation, brain biometal (Cu, Zn, Fe) dyshomeostasis); and (iii) interacts with polygenic variants relevant to LOAD. In Aim 1, we will investigate effects of early-/mid-life exposures Pb, Cd, As on AD/ADRD pathologies, phenotypes, and biomarkers in the new innovative LOAD3 mouse model (triple homozygous for humanized Aβ (hAβ), MAPT (hTau), hAPOE4). In Aim 2, we will Identify LOAD-relevant genes, proteomic networks, and molecular pathways modulated by Pb, Cd, As exposures (per Aim 1). In Aim 3, we investigate specific LOAD genetic risk factors, (variants in ABCA7, PLCG2, MTHFR) that data suggest will differentially interact with toxicant metabolism to modulate LOAD risk. Results will identify mechanisms by which common metal/metalloid neurotoxicant exposures increase risk for AD/ADRDs and prioritize novel strategies for risk reduction, disease prevention, toxicant mitigation, and therapeutic intervention for LOAD and ADRDs.