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：
10292965
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/10292965
关键词：
Acceleration Address Affect Age Age of Onset Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Americas Amyloid beta-Protein Area Astrocytes Behavior Behavioral Biochemistry Biological Availability Biological Markers Brain Chicago Chronic Cities Cognition Cognitive Complex Control Animal Coupled 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 Gene Proteins Genes Genetic Predisposition to Disease Genetic Transcription Glutamates 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 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 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 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 neuroinflammation neuropathology neurotoxic neurotoxicity presenilin-1 relating to nervous system species difference stem cell model subcutaneous tau Proteins 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.

概括知识基础上关于慢性锰的暴露如何影响发展存在基本差距 - 阿尔茨海默氏病。锰中毒的神经毒性作用以及电动机已知是其行为后遗症的障碍。但是，慢性低级暴露尚未研究。几十年来，阿尔茨海默氏病发展的神经病理学是在严重认知和疾病发作之前避免变化（痴呆症），因此其发展尤其容易受到环境影响的影响因素。锰代表一种具有很大重要性的环境毒素，因为发生了暴露通过多种来源（被污染的水，食物，污染和工业综合体吸入）。更远，暴露直接针对阿尔茨海默氏病的许多主要机制：β-淀粉样蛋白与神经炎症有关的积累，氧化应激和神经胶质变化。我们的中心假设是慢性升高锰（MN）暴露通过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如何隔离MN和认知下降之间的直接联系慢性MN暴露会影响谷氨酸清除和其他病理的改变，在小鼠和 AD的人类干细胞模型比对照组中的干细胞模型。我们将通过：（1）证明在多大程度上慢性MN暴露会加速AD神经病理学。 3个月后用MN处理显着抬高脑MN我们将评估广告相关神经病理学，氧化应激和神经素的多个标记基因，蛋白质和细胞水平的燃料编码直接假设检验和假设基因靠近。明显的β-淀粉样蛋白积累开始之前和之后，将评估变化（6- 和12个月大），以及β-淀粉样蛋白阳性（App/PSEN1，家族AD模型）和负小鼠（APOE4/TREM2，散发性AD模型；和野生型小鼠）。（2）证明慢性MN的程度暴露会影响认知能力下降。我们将使用一个年龄点评估两个年龄的学习和记忆对认知和运动变化的行为测试的预警量电池。我们将直接评估 MN影响记忆的分子基础，通过长期增强来增强突触。人类干细胞模型将用于验证这些发现。（3）确定大脑Mn水平在突触谷氨酸稳态。我们将解决MN直接影响合成谷氨酸的假设通过原发性细胞培养和干细胞模型以及评估谷氨酸摄取和释放的稳态。我们将通过电生理记录在功能上测试谷氨酸能系统。最后，我们将利用GLT-1 敲除小鼠，以进一步探测GLT-1在这种关系中的作用。这些数据将共同确认慢性MN暴露在AD神经病理学和认知能力下降中的作用，并特别解决了其影响在谷氨酸能肿瘤上。理解这些机制将突出提出al-的研究不足的作用在阿尔茨海默氏病中处理MN处理，并为疾病预防和干预提供了新的目标。