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

• 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
• 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' s Disease; Alzheimer' 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

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.

暴露在环境空气污染中与认知障碍和 心功能不全和尸检报告有证据表明 居住在环境污染水平较高的城市的人中存在淀粉样蛋白。是否 暴露在高水平的空气污染中会加速聚集体的形成 未知。我们建议对阿尔茨海默病倾向患者进行为期3个月的受控暴露实验 携带早老素-1基因(PS1ΔE9)单一突变的小鼠或 APPSWE+PS1ΔE9(APPSWE/PS1ΔE9)双突变。所有的老鼠都在 C57/Bl6J背景和C57/Bl6J野生型小鼠作为对照。老鼠会成为 从3个月大开始暴露，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 功能。将在两个时间点对小鼠进行研究：暴露后立即和 结束为期3个月的暴露。另一组小鼠将暴露在PM2.5中3个月 比FA多3个月。对照组给予FA染毒6个月。我们 假设暴露在PM2.5中的阿尔茨海默病易感小鼠将发展为：1)更大的 大脑和心脏特定解剖区域的聚集物的数量，如 通过成像和电子显微镜进行评估；2)通过 通过超声心动图、生物计量学评估行为研究和心功能 在体测量和恶化原代神经元钙稳态和 体外分离的心肌细胞的收缩功能和钙离子处理。我们也 假设暴露在PM中会通过诱导氧化来加速淀粉样蛋白病变 压力。