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

有毒金属暴露对迟发性阿尔茨海默病的新型基因小鼠模型的影响

• 批准号: 10901030
• 负责人: LEE E. GOLDSTEIN
• 金额: $ 82.26万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901030
• 关键词: Address; Adult; Affect; Airborne Particulate Matter; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Arsenic; Behavior; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Blood brain barrier dysfunction; Boston; Brain; Brain Mapping; Brain Pathology; Cadmium; Cerebrovascular Disorders; Chronic; Cognition; Cognitive deficits; Data; Dementia; Disparity; Disparity population; Dose; Elderly; Elements; Environment; Environmental Exposure; Environmental Health; Environmental Risk Factor; Exposure to; Food Contamination; Funding; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genotype; Health; Health Care Costs; Heterogeneity; High Fat Diet; Human; Human Genetics; Individual; Knowledge; Laboratories; Late Onset Alzheimer Disease; Lead; Life; Longevity; MTHFR gene; Mass Spectrum Analysis; Mediating; Metabolism; Metal exposure; Metals; Microvascular Dysfunction; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Neurotoxins; Outcome; Oxidative Stress; PLCG2 gene; Pathogenesis; Pathology; Pathway interactions; Phenotype; Prevention; Proteins; Proteomics; Research; Resolution; Resources; Risk; Risk Factors; Risk Reduction; Rural; Senile Plaques; Specimen; Structure; Systems Biology; Targeted Research; Testing; Therapeutic Intervention; Toxic Environmental Substances; Toxicant exposure; Trace Elements; Universities; Urine; Variant; Weaning; abeta accumulation; age related; aging brain; apolipoprotein E-4; blood-brain barrier permeabilization; brain health; brain tissue; chronic Pb exposure; clinically relevant; comorbidity; disease phenotype; disorder prevention; drinking water; environmental justice; experimental study; gene environment interaction; genetic risk factor; health disparity; humanized mouse; hyperphosphorylated tau; in vivo; innovation; insight; lead exposure; mass spectrometric imaging; middle age; mortality; mouse model; multidisciplinary; neuroinflammation; neuron loss; neuropathology; neurotoxic; new therapeutic target; novel; novel strategies; personalized strategies; pre-clinical research; proteomic signature; racial disparity; risk variant; sedentary lifestyle; sex; socioeconomic disparity; socioeconomics; tau Proteins; tau-1; toxic metal; toxicant; transcriptomics; uptake

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.

晚期的阿尔茨海默氏病（负载）是痴呆症的主要原因，是发病率的主要原因， 死亡率和医疗保健费用。负载大脑病理学的主要标志包括与年龄相关的积累 淀粉样蛋白β（Aβ）斑块和神经原纤维缠结（高磷酸化的tau蛋白）。遗传敏感性 因素（例如APOE4）有助于负载病理和表型，但仅占负载风险的30-70％。 研究表明，负载复杂性和异质性以及个人风险和健康结果是 遗传学和环境因素之间的相互作用调节，例如高脂饮食，久坐行为， 和生命暴露（“ exposome”）向环境有毒物质，包括铅（PB），镉（CD）和砷（AS）。 PB，CD和AS AS暴露很常见，尤其是在处境不利的人群（城市，粗糙）中，引起关注 关于负载风险差异，社会经济/种族不平等和环境正义。而PB，CD和AS 是具有已知负载缔合的神经毒素，这是这些环境的分子机制 有毒物质介导基因 - 杂糖体相互作用和调节载荷病理生物学是未知的，可能是 可修改。该项目将使用由NIA资助的Model-AD创建的创新新鼠标模型 联盟（AD-AD，U54-AG054345）与与人相关的表型，以研究如何慢性 暴露于三种普遍存在的环境神经毒性（PB，CD，AS）会影响大脑衰老和负荷风险。这 项目对一项新的NIA倡议有回应（“广告/ADRD治疗的精确环境健康方法 和预防风险”）支持临床前研究靶向介导基因环境的机制 毒物暴露效应（“ Exposome”）对AD/ADRD发病机理和利用NIA资助的AD/ADRD 资源（波士顿大学ADRC，P30-AG072978；生物态度学中心； AD型鼠标模型， 系统生物学分析，杰克逊实验室）。我们将测试我们的假设，即长期暴露于PB，CD或 就像在饮用水中一样：（i）诱导大脑中有毒金属/金属素的积累，（ii）调节与负载相关 病理/表型（ATN：Aβ，TAU蛋白质病，神经退行性，认知缺陷；血脑屏障，血脑屏障， 微血管功能障碍，神经炎症，脑生物妇女图（Cu，Zn，Fe）dyshomeostasis）; （iii）相互作用 与负载相关的多基因变体。在AIM 1中，我们将调查早期/中期暴露PB的影响， CD，如新创新负载3小鼠模型中的AD/ADRD病理，表型和生物标志物（三重 人源化Aβ（HAβ），MAPT（HTAU），HAPOE4）的纯合子。在AIM 2中，我们将确定与负载相关的基因， 蛋白质组学网络和由Pb CD调节的分子途径作为暴露（每个AIM 1）。在AIM 3中，我们 调查数据表明的特定负载遗传危险因素（ABCA7，PLCG2，MTHFR中的变体） 与毒物代谢差异相互作用以调节负载风险。结果将确定通过哪些机制 常见的金属/金属神经毒性暴露会增加AD/ADRD的风险，并优先考虑新颖的策略 降低风险，预防疾病，有毒物质减轻和负载和ADRD的治疗干预。