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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

概括关于长期接触锰如何影响发育，知识库中存在根本性差距。锰中毒对阿尔茨海默病的神经毒性作用以及运动神经毒性作用是众所周知的。然而，长期低水平暴露尚未得到研究。阿尔茨海默氏病的神经病理学在严重认知和行为障碍发作前数十年就已形成。行为变化（痴呆症）及其发展特别容易受到环境的影响锰是一种环境毒素，由于接触锰而具有很高的重要性。通过多种来源（受污染的水、食物、污染和工业园区的吸入）。暴露直接针对参与阿尔茨海默病病理学的许多主要机制：β-淀粉样蛋白与神经炎症相关的积累、氧化应激和神经胶质变化。长期接触锰 (Mn) 升高会因谷氨酸稳态受损而导致认知能力下降。我们的长期目标是通过证明锰与认知能力下降之间的直接联系慢性锰暴露在小鼠和小鼠中更大程度地影响谷氨酸清除率的改变和其他病理学 AD 的人类干细胞模型与对照组相比，我们将通过以下方式做到这一点：(1) 展示 AD 的程度。经过 3 个月的锰治疗后，慢性锰暴露会显着加速 AD 神经病理学的发展。提高大脑 Mn，我们将评估 AD 相关神经病理学、氧化应激和神经元的多种标志物基因、蛋白质和细胞水平的炎症结合了直接假设检验和假设生成将在β-淀粉样蛋白明显积累之前和之后评估变化（6- 和 12 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；和野生型小鼠）（2）证明慢性 Mn 的程度。我们将使用计算机评估两个年龄点的学习和记忆能力。我们将直接评估认知和运动变化的潜力。锰影响记忆的分子基础，通过长期增强人类突触。 (3) 确定脑锰水平在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保持体内平衡，并评估谷氨酸的吸收和释放。将通过电生理记录对谷氨酸能系统进行功能测试最后我们将利用 GLT-1。基因敲除小鼠进一步探讨 GLT-1 特别是在这种关系中的作用，这些数据将共同证实。慢性锰暴露在 AD 神经病理学和认知能力下降中的作用，并具体阐述其影响了解这些机制将凸显对谷氨酸能失调的作用。提出了锰在阿尔茨海默病中的作用，并为疾病预防和干预提供了新的目标。