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.

阿尔茨海默病（AD）的病因和发病机制是多因素的，包括遗传、环境等。 以及与年龄相关的因素共同导致神经退行性变以及认知和行为异常。 慢性锰 (Mn) 过度暴露影响的分子机制与 神经退行性变，可能直接导致和/或加速 AD 病理学和临床痴呆。 使用最先进的分析工具进行的分析研究将用于定义暴露引起的机制 兴奋性毒性特性并探索干预认知相关途径的机会 该项目的主要目标是皮质和纹状体脑组织的功能和神经病理学变化。 在分子水平（代谢物和脂质）了解之间的生化机制 慢性锰暴露和AD神经病理学我们的重点是谷氨酸能和AD的失调。 多巴胺能神经递质系统，但靶向和非靶向方法将识别多个 这些知识将用于确定哪些机制可能是潜在的。 我们的数据将通过营养或药物干预来减缓认知能力下降。 还确定了与认知能力下降比经典标志特征更密切相关的变化 AD（β-淀粉样蛋白和神经原纤维缠结）我们的首要假设是，AD 相关的代谢是关键。 途径对外部暴露有反应，那么它们是可塑的，并且针对这些途径可能 在两个独立的具体目标中的第一个中，提供了减缓大脑 AD 发病或进展的新途径。 我们将确定表明神经病理学和行为变化的代谢组学和脂质组学变化 通过饮食暴露于低锰或高锰的 APP/PSEN1 小鼠我们将使用皮质和纹状体（可用的组织）。 通过 R01 ES031401）了解已知可积累 Mn 的两个相关区域的变化 具有最先进的代谢物和脂质化学测定的不同方面。 概况将用于确定哪些途径受锰暴露影响最大，并确定是否 组织类型（纹状体和皮层）存在差异，我们将通过特定目标 2 确定哪一种。 谷氨酸代谢途径的成员因长期接触锰而失调，通过靶向LC- 对目标 1 中使用的相同组织进行 MS/MS 分析。具体来说，这些研究将使我们能够确定 典型谷氨酸代谢途径的特定成员以及氧化还原稳态， 三羧酸（TCA）循环以及丙氨酸和天冬氨酸途径上调或下调以响应 慢性锰暴露可进一步了解锰在 AD 和正常衰老大脑中引起的兴奋性毒性。 所有发现都将与通过该系统生成的行为、神经病理学和生化数据相关联。 母体 R01 来询问代谢失调的功能结果。

项目成果

Current Practices in LC-MS Untargeted Metabolomics: A Scoping Review on the Use of Pooled Quality Control Samples.

LC-MS 非靶向代谢组学的当前实践：对混合质量控制样品使用的范围界定审查。

• 发表时间: 2023-12-26
• 影响因子: 7.4
• 作者: Broeckling, Corey D;Beger, Richard D;Cheng, Leo L;Cumeras, Raquel;Cuthbertson, Daniel J;Dasari, Surendra;Davis, W Clay;Dunn, Warwick B;Evans, Anne Marie;Fernández;Gika, Helen;Goodacre, Royston;Goodman, Kelli D;Gouveia, Goncalo J
• 通讯作者: Gouveia, Goncalo J

Improving confidence in lipidomic annotations by incorporating empirical ion mobility regression analysis and chemical class prediction.

通过结合经验离子淌度回归分析和化学类别预测，提高脂质组学注释的可信度。

• 发表时间: 2022-05-13
• 作者: Rose, Bailey S;May, Jody C;Picache, Jaqueline A;Codreanu, Simona G;Sherrod, Stacy D;McLean, John A
• 通讯作者: McLean, John A

Improving Confidence In Lipidomic Annotations By Incorporating Empirical Ion Mobility Regression Analysis And Chemical Class Prediction.

通过结合经验离子淌度回归分析和化学类别预测来提高脂质组学注释的可信度。

• 发表时间: 2022-03-31
• 作者: Rose, Bailey S;May, Jody C;Picache, Jaqueline A;Codreanu, Simona G;Sherrod, Stacy D;McLean, John A
• 通讯作者: McLean, John A