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

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 以及与年龄相关的因素，这些因素共同推动神经退化以及认知和行为的下降。异常 慢性锰(Mn)过量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病理和临床痴呆。全球 将使用最先进的分析工具进行侧写研究，以确定暴露诱导的机制 兴奋性毒性的特性和探索对与认知相关的改变的通路进行干预的机会 皮质和纹状体脑组织的功能和神经病理变化。这个项目的主要目标是 从分子水平(代谢物和脂类)了解 慢性锰暴露与阿尔茨海默病神经病理我们的关注点是谷氨酸能和 多巴胺能神经递质系统，但靶向和非靶向方法将识别多个 新的和有针对性的路径。这一知识将用于确定哪些机制可能 通过营养或药物干预来减缓认知衰退。我们的数据将 也要找出与认知能力下降有更密切关系的变化，而不是 AD(β-淀粉样蛋白和神经原纤维缠结)。我们的主要假设是，如果与AD相关的关键代谢 通路对外部暴露有反应，然后它们是可塑性的，并且靶向这些通路可能 为延缓大脑中AD的发病或进展提供新的途径。在两个独立的具体目标中的第一个 我们将确定指示神经病理和行为变化的代谢和脂体变化 APP/PSEN1小鼠通过饮食暴露于低、高锰水平。我们将使用皮质和纹状体(可用的组织 通过R01 ES031401)，以了解两个已知积累锰的区域的变化，这两个区域 行为改变的不同方面。代谢物和脂类的最新化学测定方法 将使用图谱来确定哪些途径受到锰暴露的影响最大，并确定是否 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 慢性锰暴露通过靶向LC-2调节谷氨酸代谢途径的成员 对目标1中使用的相同组织进行MS/MS分析。具体地说，这些研究将使我们能够确定 典型的谷氨酸代谢途径的哪些特定成员，以及氧化还原动态平衡， 三羧酸(TCA)循环和丙氨酸、天冬氨酸途径上调或下调是对 进一步了解慢性锰暴露对阿尔茨海默病和正常衰老大脑的兴奋性毒性作用。 所有的发现都将与行为、神经病理和生化数据相关 亲本R01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.