Gene Interactions in a Model of Alzheimer's Disease

阿尔茨海默病模型中的基因相互作用

• 批准号: 8066971
• 负责人: FRANK M LAFERLA
• 金额: $ 28.99万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066971
• 关键词: Age; Agreement; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Animal Model; Binding; Brain; Clinical; Clinical Data; Cognition; Cognitive; Comorbidity; Coronary heart disease; Data; Dementia; Development; Diabetes Mellitus; Diet; Disease; Educational Background; Elderly; Exhibits; Genetic; Glucocorticoids; Goals; Hormones; Human; Hydrocortisone; Immunotherapy; Impaired cognition; Individual; Investigation; Ischemia; Lead; Lewy Bodies; Link; Memory impairment; Molecular; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic; Osteoporosis; Parkinson Disease; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Physical activity; Play; Population; Prevalence; Process; Regimen; Reporting; Risk Assessment; Risk Factors; Role; Severities; Signal Pathway; Stress; Stroke; Symptoms; Time; Transgenes; Variant; age related; aged; alpha synuclein; beta-site APP cleaving enzyme 1; clinically relevant; disease phenotype; gene interaction; hypothalamic-pituitary-adrenal axis; interest; mouse model; mutant; nervous system disorder; neuropathology; new therapeutic target; synuclein; tau Proteins

DESCRIPTION (provided by applicant): Besides age, many other factors are thought to influence the onset and progression of Alzheimer's disease (AD), including genetics, diet, stress, education level, physical activity, and other neurological disease. Here we seek to evaluate the effects of such co-morbidities on AD. This application proposes to utilize a systematic approach toward elucidating the effects of co-morbid conditions on AD neuropathology and cognitive phenotype in the 3xTg-AD mouse model. We propose to study three common co-morbid conditions that are clinically relevant, amenable to study in a lab setting, and for which we already have substantial preliminary data. AIM 1. Stress as a co-morbidity that influences AD pathology. Stress is a risk factor for AD We recently reported that stress-level glucocorticoids increase APP, BACE, and A¿ levels as well as augmenting tau. Here we propose to evaluate the effects of physiologically-relevant stress paradigms on AD pathology and cognition in 3xTg-AD mice. AIM 2. Determine the impact of global ischemic stress on A¿ and tau pathology. Here we will investigate the link between ischemic stress and the development of AD pathologies. Our preliminary data show that global ischemic insults have diverse temporal effects on both A¿ and tau pathology. We propose to fully elucidate these effects and explore the underlying molecular mechanisms that occur during and after ischemia which impact pathology. We seek to identify novel therapeutic targets, as we have found that ischemia leads to the rapid clearance of somatodendritic tau via lysosomal degradation. By exploring the triggers and taubinding partners involved, we can uncover signaling pathways that lead to the clearance of somatodendritic tau. Ultimately, our preliminary data show, in agreement with clinical data and other studies, that ischemia leads to an increase in AD related pathologies. The implications of this study are significant as ischemia is a prevalent feature among the elderly population and it is critical to determine its effects on the AD phenotype. Aim 3: Synergistic interactions among A¿, tau and a-synuclein. Up to 50% of AD cases exhibit a- synuclein immunoreactive Lewy Bodies in addition to plaques and tangles (Raghavan et al., 1993; Hamilton, 2000). This common co-morbidity promotes an aggressive disease course and accelerates cognitive decline (Hansen et al., 1990; Langlais et al., 1993). Our preliminary data indicate that introducing a mutant a- synuclein transgene, as a way to induce LB formation in the brains of an AD mouse model, exacerbates the neuropathological and cognitive phenotype. We are now poised to determine whether A¿-directed therapies, such as A¿ immunotherapy, will be effective in rescuing the cognitive decline in mice that also harbor Lewy body pathology. This aim is significant as it represents one of the first attempts to determine if currently pursued strategies against AD will be effective in patients with other forms of A¿ dementia (i.e., Lewy body variant).PUBLIC HELATH RELEVANCE: Alzheimer's disease (AD) is the common age-related neurodegenerative disorder, and at present there is no cure. Unfortunately, the aged population is not only susceptible to AD but they also frequently succumb to other ailments that can influence its progression and severity. These other disorders can be considered co-morbidities, and surprisingly, there has not been a systematic investigation into the effects of co-morbidities on the progression of AD in animal models. This proposal seeks to determine the impact that co-morbidities such as ischemia and stress play on the development of AD in the 3xTg-AD mouse model.

描述（由应用提供）：除了年龄外，许多其他因素被认为会影响阿尔茨海默氏病（AD）的发作和进展，包括遗传学，饮食，压力，教育水平，体育活动和其他神经系统疾病。在这里，我们试图评估此类合并症对AD的影响。 3XTG-AD小鼠模型中的认知表型。我们建议研究三种在临床上相关的常见合并症，可以在实验室环境中进行研究，并且我们已经拥有大量的初步数据。目的1。压力是影响AD病理的合并症。压力是AD的危险因素，我们最近报告说，应力水平的糖皮质激素会增加应用，乳胶和A水平以及增加TAU。在这里，我们建议评估与物理相关的应激范例对3XTG-AD小鼠AD病理学和认知的影响。目标2。确定全球缺血性压力对A a和tau病理的影响。在这里，我们将研究缺血性压力与AD病理发展之间的联系。我们的初步数据表明，全球缺血性损害对A a和Tau病理都有潜水员的暂时影响。我们建议充分阐明这些作用，并探索影响病理学期间和缺血期间发生的基本分子机制。我们试图确定新颖的治疗靶标，因为我们发现缺血导致通过溶酶体降解快速清除体长tau。通过探索涉及的触发伴侣和陶织式伴侣，我们可以发现导致Somatendendritic Tau清除的信号通路。最终，我们的初步数据表明，与临床数据和其他研究一致，缺血导致与AD相关的病理增加。这项研究的含义很重要，因为缺血是老年人群中普遍的特征，并且确定其对AD表型的影响至关重要。 AIM 3：A？，TAU和A-核蛋白之间的协同相互作用。除斑块和缠结外，多达50％的AD病例暴露了A-突触核蛋白免疫反应性Lewy体（Raghavan等，1993; Hamilton，2000）。这种常见的合并症促进了侵略性疾病病程并加速了认知能力下降（Hansen等，1990； Langlais等，1993）。我们的初步数据表明，引入突变体A-核蛋白转化，是一种诱导AD小鼠模型大脑中LB形成的方式，加剧了神经病理学和认知表型。现在，我们被中毒以确定A领导的疗法（例如A免疫疗法）是否有效地挽救了携带Lewy身体病理学的小鼠的认知能力下降。该目标是重要的，因为它代表了确定当前采取针对AD的策略是否有效的尝试之一，对于其他形式的A痴呆症患者（即Lewy身体变体）。公共Helath的相关性：阿尔茨海默氏病（AD）是常见的年龄相关的神经性疾病，目前没有疗效。不幸的是，老年人口不仅容易受到AD的影响，而且还经常屈服于可能影响其进展和严重性的其他疾病。这些其他疾病可以视为合并症，令人惊讶的是，对合并症对动物模型中AD进展的影响尚未进行系统的研究。该提案旨在确定3xTG-AD小鼠模型中的合并症（等缺血和压力对AD发展的影响）的影响。