Manganese exposure susceptibility as a modifier of excitotoxicity in Alzheimer's Disease

锰暴露敏感性作为阿尔茨海默病兴奋性毒性的调节剂

• 批准号: 10514587
• 负责人: Aaron B Bowman
• 金额: $ 53.56万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10514587
• 关键词: Acceleration; Address; Affect; Age; Age Months; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Area; Astrocytes; Autopsy; Behavior; Behavioral; Biochemistry; Biological Availability; Biological Markers; Brain; Cell Culture Techniques; Chicago; Chronic; Cities; Cognition; Cognitive; Complex; Control Animal; Coupled; Cultured Cells; Data; Dementia; Development; Diet; Diffuse; Disease; Disease Marker; Disease Progression; Electroencephalography; Electrophysiology (science); Environment; Environmental Risk Factor; Epilepsy; Epileptogenesis; Equilibrium; Exposure to; Expression Profiling; Food; Future; Gasoline; Genes; Genetic Predisposition to Disease; Genetic Transcription; Glutamates; Heterozygote; Homeostasis; Human; Immunohistochemistry; Impaired cognition; Impairment; Incidence; Industrialization; Inflammation; Inflammatory; Inhalation; Intervention; Kainic Acid; Knockout Mice; Learning; Life; Link; Long-Term Potentiation; Macaca; Manganese; Manganese Poisoning; Mass Spectrum Analysis; Measures; Memory; Methods; Mexico; Mission; Molecular; Motor; Mus; Mutation; National Institute of Environmental Health Sciences; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuronal Differentiation; Neurons; Neurotoxins; Neurotransmitters; Occupational Exposure; Onset of illness; Oral; Outcome; Oxidation-Reduction; Oxidative Stress; Parkinsonian Disorders; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Plants; Pollution; Population Control; Predisposition; Primary Cell Cultures; Primates; Proteins; Public Health; Publishing; Regulatory Pathway; Research; Rodent; Role; Sampling; Seizures; Senile Plaques; Severities; Signal Transduction; Social Functioning; Source; Speed; Symptoms; Synapses; System; TREM2 gene; Techniques; Telemetry; Testing; Therapeutic; Tissues; Toxic Environmental Substances; Toxic effect; Tremor; Wild Type Mouse; Work; abeta accumulation; apolipoprotein E-4; arginase; behavior test; burden of illness; cognitive change; cognitive testing; contaminated water; disorder prevention; emotional functioning; epidemiologic data; epidemiology study; excitotoxicity; experimental study; exposed human population; familial Alzheimer disease; glutamatergic signaling; human data; human stem cells; hyperphosphorylated tau; induced pluripotent stem cell; inflammatory marker; knowledge base; middle age; mild cognitive impairment; molecular marker; motor control; motor impairment; mouse model; neural; neuroinflammation; neuropathology; neurotoxic; neurotoxicity; presenilin-1; species difference; stem cell model; subcutaneous; uptake; young adult

SUMMARY There is a fundamental gap in the knowledge base about how chronic manganese exposures impacts develop- ment of Alzheimer’s disease. The neurotoxic effects of manganese poisoning are known, as well as the motor impairments that are its behavioral sequelae. However, chronic lower-level exposures have not been studied. The neuropathology of Alzheimer’s disease develops over decades prior to onset of severe cognitive and be- havioral change (dementia) and thus its development is particularly susceptible to influence from environmental factors. Manganese represents an environmental toxin with high likelihood of importance since exposure occurs through multiple sources (contaminated water, food, inhalation from pollution and industrial complexes). Further, exposure directly targets many of the primary mechanisms involved in Alzheimer’s disease pathology: β-amyloid accumulation, oxidative stress and glial changes relating to neuroinflammation. Our central hypothesis is that Chronic elevated manganese (Mn) exposure drives cognitive decline through impaired glutamate homeostasis. Our long-term objectives are to isolate the direct link(s) between Mn and cognitive decline by demonstrating how chronic Mn exposure affects altered glutamate clearance and other pathologies to a greater extent in mouse and human stem cell models of AD than in controls. We will do this by: (1) Demonstrating the extent to which chronic Mn exposure accelerates AD neuropathology. Following 3 months treatment with Mn to significantly elevate brain Mn we will assess multiple markers of AD-related neuropathology, oxidative stress and neuroin- flammation at the gene, protein and cellular level incorporating direct hypothesis testing and hypothesis gener- ating approaches. Changes will be assessed prior to- and after onset of significant β-amyloid accumulation (6- and 12 months of age), and in β-amyloid positive (APP/PSEN1, familial AD model) and negative mice (APOE4/TREM2, sporadic AD model; and wild-type mice). (2) Demonstrating the extent to which chronic Mn exposure impacts cognitive decline. We will assess learning and memory at the two age points using a com- prehensive battery of behavioral tests for cognitive and motor changes. We will directly assess the potential for Mn to impact the molecular basis of memory, synaptic strengthening through long term potentiation. Human stem cell models will be utilized to validate these findings. (3) Establishing the role of brain Mn levels in synaptic glutamate homeostasis. We will address the hypothesis that Mn directly impacts synaptic glutamate homeostasis through primary cell culture and stem cell models and assess glutamate uptake and release. We will functionally test the glutamatergic system by electrophysiological recordings. Finally we will utilize GLT-1 knockout mice to further probe the role of GLT-1 in particular in this relationship. Together these data will confirm the role of chronic Mn exposure in AD neuropathology and cognitive decline, and specifically address its impact on glutamatergic dyshomeostasis. Understanding these mechanisms will highlight an under-studied role for al- tered Mn handling in Alzheimer’s disease, and provide a new target for disease prevention and interventions.

摘要 关于慢性接触锰的影响是如何发展的，在知识基础上存在一个根本性的缺口- 阿尔茨海默氏症的症状。众所周知，锰中毒的神经毒性效应以及马达。 这是它的行为后遗症。然而，慢性低水平暴露还没有被研究过。 阿尔茨海默病的神经病理学在严重的认知和BE发作之前几十年就已经发展起来。 行为变化(痴呆症)及其发展特别容易受到环境的影响 各种因素。锰是一种环境毒素，由于接触到锰的可能性很高。 通过多种来源(受污染的水、食物、来自污染的吸入和工业园区)。此外， 暴露直接针对阿尔茨海默病病理中涉及的许多主要机制：β-淀粉样蛋白 蓄积、氧化应激和与神经炎症相关的神经胶质变化。我们的中心假设是 慢性高锰暴露通过破坏谷氨酸稳态而导致认知能力下降。 我们的长期目标是通过证明MN和认知功能减退之间的直接联系(S) 慢性锰暴露在更大程度上影响小鼠和小鼠谷氨酸清除和其他病理改变 阿尔茨海默病的人类干细胞模型比对照组的要好。我们将通过以下方式做到这一点：(1)展示 慢性锰暴露可加速AD的神经病理。在使用锰治疗3个月后，显著 我们将评估AD相关神经病理、氧化应激和神经蛋白的多个标记物。 在基因、蛋白质和细胞水平上的燃烧结合了直接假设检验和假设生成- 正在接近。将在显著的β-淀粉样蛋白堆积开始之前和之后评估变化(6- 和12个月龄)，以及β淀粉样蛋白阳性(APP/PSEN1，家族性AD模型)和阴性小鼠 (ApoE4/TREM2，散发性AD模型；野生型小鼠)。(2)显示慢性锰中毒的程度 暴露会影响认知能力下降。我们将使用COM来评估两个年龄点的学习和记忆 对认知和运动变化进行全面的行为测试。我们将直接评估潜在的 MN影响记忆的分子基础，通过长时程增强加强突触。人类 干细胞模型将被用来验证这些发现。(3)确定脑内锰水平在脑内的作用 突触谷氨酸动态平衡。我们将讨论锰直接影响突触谷氨酸的假设。 通过原代细胞培养和干细胞模型实现动态平衡，并评估谷氨酸的摄取和释放。我们 将通过电生理记录对谷氨酸能系统进行功能性测试。最后，我们将使用GLT-1 进一步探讨GLT-1在这一关系中的作用。这些数据加在一起将证实 慢性锰暴露在阿尔茨海默病神经病理和认知功能下降中的作用，并具体阐述其影响 关于谷氨酸能代谢紊乱。了解这些机制将突显出基地组织在其中的作用尚未得到充分研究。 本研究为阿尔茨海默病的治疗提供了新的靶点。