Understanding metabolic changes associated with chronic manganese exposure and Alzheimer's Disease

了解与慢性锰暴露和阿尔茨海默病相关的代谢变化

• 批准号: 10353617
• 负责人: Fiona Edith Harrison
• 金额: $ 17.71万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10353617
• 关键词: Affect; Age; Air Pollution; Alanine; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Animal Model; Animals; Antioxidants; Area; Aspartate; Attention; Award; Behavioral; Biochemical; Biochemistry; Biological; Biological Assay; Biological Markers; Biological Process; Brain; Cell Death; Chemicals; Chronic; Clinical; Cognitive; Complex; Control Animal; Corpus striatum structure; Data; Databases; Dementia; Detection; Development; Diet; Disease; Disease Progression; Dopamine; Energy Metabolism; Environment; Equilibrium; Etiology; Exposure to; Fumarates; Functional disorder; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genotype; Glutamate Metabolism Pathway; Glutamate-Ammonia Ligase; Glutamates; Goals; Heterogeneity; Homeostasis; Human; Impaired cognition; Individual; Intervention; Knowledge; Length; Link; Lipids; Liquid Chromatography; Literature; Manganese; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Pathway; Methods; Micronutrients; Midbrain structure; Molecular; Molecular Abnormality; Molecular Analysis; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neuropsychological Tests; Neuropsychology; Neurotransmitters; Occupational Exposure; Onset of illness; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Pathway; Parents; Pathogenesis; Pathway interactions; Pharmacology; Population; Prevention; Process; Property; Regulation; Relative Risks; Resolution; Role; SOD2 gene; Sampling; Succinates; System; Testing; Tissues; Transgenic Mice; Water Pollution; Weaning; Work; abeta accumulation; abeta deposition; age related; aged; aging brain; alpha ketoglutarate; base; brain tissue; cofactor; cognitive function; effective therapy; excitotoxicity; functional outcomes; human imaging; immune function; improved; interest; lipidomics; member; metabolome; metabolomics; mouse model; nerve supply; neurobehavioral; neuroinflammation; neuropathology; neurotoxic; normal aging; novel; nutrition; presenilin-1; relating to nervous system; response; sex; standard measure; tau Proteins; tool

The etiology and pathogenesis of Alzheimer’s disease (AD) are multifactorial including genetic, environmental and age-related factors that together drive neurodegeneration and cognitive and behavioral declines. Abnormal molecular mechanisms impacted by chronic manganese (Mn) overexposure have been associated with neurodegeneration and may directly contribute to and/or accelerate AD pathology and clinical dementia. Global profiling studies using state-of-the-art analysis tools will be used to define mechanisms of exposure-induced excitotoxity properties and to explore opportunities for intervention on altered pathways related to cognitive function and neuropathological change in cortex and striatum brain tissue. The primary goal of this project is to understand at the molecular level (metabolites and lipids) the biochemical mechanisms between chronic manganese exposure and AD neuropathology. Our focus is dysregulation of glutamatergic and dopaminergic neurotransmitter systems but the targeted and non-targeted approaches will identify multiple novel and targetable pathways. This knowledge will be used to determine which mechanisms may potentially be manipulated by nutrition or pharmacological interventions in order to slow cognitive decline. Our data will also identify changes that may relate more strongly to cognitive decline than the classical hallmark features of AD (β-Amyloid and neurofibrillary tangles). Our overarching hypothesis is that if key AD-relevant metabolic pathways are responsive to external exposures then they are malleable and targeting these pathways may provide new avenues to slow AD onset or progression in the brain. In the first of two independent Specific Aims we will identify metabolomic and lipidomic changes indicative of neuropathological and behavioral change in APP/PSEN1 mice exposed to low or high Mn through diet. We will use cortex and striatum (tissues available through R01 ES031401) to understand changes in two areas known to accumulate Mn, that are associated with different aspects of behavioral change. State-of-the-art chemical determination of metabolite and lipid profiles will be used to identify which pathways are most impacted by manganese exposure, and determine if there are differences in tissue type (striatum and cortex). Through Specific Aim 2 we will determine which members of the glutamate metabolism pathway are dysregulated by chronic Mn exposure via targeted LC- MS/MS analyses on the same tissues utilized in Aim 1. Specifically, these studies will allow us to determine which specific members of the canonical glutamate metabolism pathway, as well as redox homeostasis, the tricarboxylic (TCA) cycle and the alanine, and aspartate pathways are up- or down-regulated in response to chronic Mn exposure to further our understanding of Mn-induced excitotoxicity in AD and normal aging brains. All findings will be correlated with behavioral, neuropathological and biochemical data generated through the parent R01 to interrogate functional outcomes of metabolic dysregulation.

阿尔茨海默氏病（AD）的病因和发病机理是多因素的，包括遗传，环境 以及与年龄相关的因素，这些因素共同驱动神经变性，认知和行为下降。异常 受慢性锰（MN）过度暴露影响的分子机制与 神经变性，可能直接有助于和/或加速AD病理学和临床痴呆。全球的 使用最先进的分析工具进行分析研究将用于定义暴露诱导的机制 兴奋性特性并探索与认知有关的改变途径的干预机会 皮质和纹状体脑组织的功能和神经病理学变化。这个项目的主要目标是 要了解分子水平（代谢产物和脂质）的生化机制 慢性锰暴露和AD神经病理学。我们的重点是谷氨酸能的失调和 多巴胺能神经递质系统，但目标和非目标方法将识别多个 新颖且可定位的途径。这些知识将用于确定哪些机制可能有可能 通过营养或药物干预措施来操纵，以减慢认知能力下降。我们的数据将 还要确定可能与认知下降更加强烈的变化，而不是经典的标志特征 AD（β-淀粉样蛋白和神经原纤维缠结）。我们的总体假设是，如果与关键广告相关的代谢 途径对外部暴露有反应 提供新的途径，以减慢大脑的AD发作或进展。在两个独立的特定目标中的第一个 我们将确定代谢组和脂肪组学变化，指示神经病理学和行为变化 通过饮食暴露于低或高MN的APP/PSEN1小鼠。我们将使用皮层和纹状体（可用的组织 通过R01 ES031401）了解已知累积MN的两个区域的变化， 行为改变的不同方面。代谢物和脂质的最先进的化学测定 配置文件将用于确定哪些途径受到锰的影响最大的途径，并确定是否是否 组织类型（纹状体和皮层）存在差异。通过特定目标2，我们将确定哪个 谷氨酸代谢途径的成员通过靶向LC-的慢性MN暴露而失调 在AIM 1中使用的相同组织的MS/MS分析。具体来说，这些研究将使我们能够确定 规范谷氨酸代谢途径的哪些特定成员以及氧化还原稳态的哪个 三核（TCA）循环和丙氨酸和天冬氨酸途径响应于上调或下调 慢性MN暴露于我们对AD和正常衰老大脑中MN诱导的兴奋性毒性的理解。 所有发现将与通过该行为，神经病理学和生化数据相关 父R01询问代谢失调的功能结果。