Mechanisms of exposure-induced tissue functional and pathological changes in a mouse model of Alzheimer's Disease

阿尔茨海默病小鼠模型暴露引起的组织功能和病理变化的机制

基本信息

批准号：
9908035
负责人：
Colin K Combs
金额：
$ 76.16万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908035
关键词：
Affect Age Aging Air Pollution Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Anatomy Area Atherosclerosis Atrophic Autopsy Belief Biochemical Biometry Blood Vessels Blood flow Brain Brain Diseases Brain region Calcium Calcium Signaling Cardiac Cardiac Myocytes Cardiac Output Cardiovascular Diseases Cardiovascular system Cause of Death Cerebrum Cessation of life Cities Clinical Research Control Groups Degenerative Disorder Dementia Development Disease Echocardiography Elderly Electron Microscopy Epidemiology Exons Exposure to Functional disorder Gene Proteins Genes Genetic Growth Head Heart Heart Diseases Heart failure Hippocampus (Brain)Histology Homeostasis Hypoxia Image Impaired cognition Impairment In Vitro Individual Link Measurement Mediating Metabolic Modeling Molecular Biology Morbidity - disease rate Mus Mutation Myocardial Myocardial dysfunction Myocardium Neurons New England New York Organ Oxidative Stress Particulate Matter Pathogenesis Pathogenicity Pathologic Pathology Patients Physiological Plague Plasma Pollution Presenile Alzheimer Dementia Prevalence Primary idiopathic dilated cardiomyopathy Process Reporting Risk Factors Role Structure Swedish mutation Symptoms Temporal Lobe Testing Time Tissues Transgenic Mice Wild Type Mouse World Health Organization age related aging population air filter ambient air pollution amyloid pathology behavior test behavioral study body system brain parenchyma cardiovascular health cognitive function experimental study fine particles frontal lobe genetic variant heart function human old age (65+)hypoperfusion improved in vivo in vivo evaluation mortality mouse model neuron loss pathological aging presenilin presenilin-1 prospective protein aggregation risk sharing

项目摘要

Exposure to ambient air pollution has been associated with both cognitive impairment and cardiac dysfunction and a post-mortem study reported evidence of accumulation of amyloid among people living in cities with high levels of ambient pollution. Whether exposure to high levels of air pollution accelerates the formation of aggregates is unknown. We propose a 3 month controlled exposure experiment in Alzheimer’s prone mice carrying the single mutation in the in the Presenilin-1 gene (PSEN1) (PS1ΔE9) or the double mutation in the APPswe + the PS1ΔE9 (APPswe/PS1ΔE9). All mice are in the C57/Bl6J background and C57/Bl6J wild-type mice will serve as controls. Mice will be exposed beginning at age 3 months to evaluate the impact of concentrated fine particulate matter (PM2.5) versus filtered air (FA) exposure on brain and cardiac structure and function. Mice will be studied at two time points: immediately after the exposure and at the end of the 3-month exposure. Another set of mice will be exposed to PM2.5 for 3 month than for FA for 3 more months. A control group will be exposed to FA for 6 month. We hypothesize that Alzheimer’s prone mice exposed to PM2.5 will develop: 1) a greater quantity of aggregates in the specific anatomical regions of the brain and heart as assessed by imaging and electron microscopy; 2) worsen brain function assessed with behavioral studies and cardiac function assessed by echocardiography, biometric measurements in-vivo and worsen calcium homeostasis in primary neurons and contractile function and calcium handling in isolated cardiomyocytes in-vitro. We also hypothesize that exposure to PM will accelerate amyloid pathology by inducing oxidative stress.

暴露于环境空气污染与认知障碍和心脏功能障碍和尸检研究报告了心脏功能障碍积累的证据居住在环境污染严重的城市的人群中是否存在淀粉样蛋白。暴露于高浓度的空气污染中会加速聚集物的形成未知。我们建议对阿尔茨海默氏症患者进行为期 3 个月的受控暴露实验。携带 Presenilin-1 基因 (PSEN1) (PS1ΔE9) 单突变的小鼠或 APPswe + PS1ΔE9 (APPswe/PS1ΔE9) 中的双重突变。 C57/Bl6J 背景小鼠和 C57/Bl6J 野生型小鼠将作为对照。从 3 个月大时开始暴露，以评估浓缩细颗粒物的影响物质 (PM2.5) 与过滤空气 (FA) 暴露对大脑和心脏结构的影响小鼠的功能将在两个时间点进行研究：暴露后立即和暴露后。 3 个月暴露结束后，另一组小鼠将暴露于 PM2.5 3 个月。比 FA 多 3 个月，对照组将接触 FA 6 个月。暴露于 PM2.5 的小鼠会增加患阿尔茨海默病的风险：1) 大脑和心脏特定解剖区域中聚集体的数量通过成像和电子显微镜评估；2) 脑功能恶化通过超声心动图、生物识别评估行为研究和心脏功能体内测量并加深初级神经元的钙稳态我们还研究了体外分离心肌细胞的收缩功能和钙处理。接触 PM 会通过诱导氧化加速淀粉样蛋白病理学压力。