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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：
10090601
负责人：
Aaron B Bowman
金额：
$ 51.82万
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/10090601
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.

总结