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

阿尔茨海默病（Alzheimer's disease，AD）的病因和发病机制是多因素的，包括遗传、环境和免疫等 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下降。异常 受慢性锰（Mn）过量影响的分子机制与 并且可能直接导致和/或加速AD病理学和临床痴呆。全球 将使用最先进的分析工具进行分析研究，以确定 兴奋性毒性特性，并探索干预与认知相关的改变途径的机会。 皮质和纹状体脑组织功能和神经病理改变。该项目的主要目标是 在分子水平上（代谢物和脂质）了解 慢性锰暴露和AD神经病理学。我们的重点是肾上腺素能的失调， 多巴胺能神经递质系统，但靶向和非靶向方法将确定多种 新的和有针对性的途径。这些知识将用于确定哪些机制可能 通过营养或药物干预来控制，以减缓认知能力下降。我们的数据将 还确定了可能与认知衰退相关的变化，而不是与认知衰退的经典标志性特征相关的变化。 AD（β-淀粉样蛋白和神经纤维缠结）。我们的总体假设是，如果关键的AD相关代谢 通路对外部暴露有反应，那么它们是可塑的，靶向这些通路可以 为减缓AD在大脑中的发作或进展提供了新的途径。在两个独立的具体目标的第一个中， 我们将确定代谢组学和脂质组学的变化，这些变化指示神经病理学和行为学的变化， APP/PSEN 1小鼠通过饮食暴露于低或高Mn。我们将使用皮质和纹状体（可用的组织） 通过R 01 ES 031401），了解已知积累Mn的两个区域的变化， 行为改变的不同方面。代谢物和脂质的最新化学测定 将使用这些曲线来确定哪些途径受锰暴露的影响最大，并确定 在组织类型（纹状体和皮质）上存在差异。通过具体目标2，我们将确定 谷氨酸代谢途径的成员通过慢性锰暴露通过靶向LC- 目标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 典型的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响应于 慢性锰暴露，以进一步了解锰诱导的兴奋性毒性在AD和正常老化的大脑。 所有的发现都将与行为，神经病理学和生化数据相关联，这些数据是通过 父母R 01询问代谢失调的功能结果。

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.