Peripheral & Brain Cholesterol Metabolism in Neurodegenerative Mouse Models

周边

基本信息

批准号：
9041470
负责人：
Nicholas Francis Fitz
金额：
$ 9.26万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9041470
关键词：
ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Adenovirus Vector Affect Age Agonist Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid Apolipoprotein A-I Apolipoprotein E Apolipoproteins Apolipoproteins A Astrocytes Binding Blood Vessels Brain Brain imaging Cells Cerebral Amyloid Angiopathy Cholesterol Cholesterol Homeostasis Clinical Cognition Complex Dementia Deposition Disease Progression Etiology Excision Genetic Health High Density Lipoproteins Homeostasis Human Image Immunization Impaired cognition In Vitro Knock-in Mouse Knock-out Knockout Mice Label Late Onset Alzheimer Disease Learning Life Link Lipids Lipoproteins Liver Liver X Receptor Mediating Membrane Protein Traffic Microscopy Minority Molecular Chaperones Mus Mutation Nerve Degeneration Neurofibrillary Tangles Neurons Pathology Peripheral Phenotype Predisposition Procedures Process Production Proteins RXR Research Risk Risk Factors Role Route Senile Plaques Serum Structure Techniques Therapeutic Time Tissues Toxic effect Training Transgenic Mice Up-Regulation Viral Vector Woman amyloid pathology amyloid precursor protein processing base brain parenchyma clinically significant design genetic risk factor high risk improved in vivo insight mouse model neuropathology overexpression particle responsible research conduct

项目摘要

DESCRIPTION (provided by applicant): Sporadic Alzheimer's disease (AD) is a late-onset dementia of unknown etiology, characterized by the presence of amyloid b (A?) containing senile plaques, neurofibrillary tangles, and cognitive decline. Importantly, the inheritance of Apolipoprotein (APOE) allele is the only established risk factor for sporadic late onset AD. However, the mechanism underlying this association remains elusive. ATP binding cassette transporter A1 (ABCA1) regulates cholesterol efflux from cells to cholesterol acceptors, primarily poorly lipidated apolipoprotein A-I (APOA-I) and APOE thus generating nascent high density lipoprotein (HDL). Disruption of Abca1 in APP expressing mice increased plaque levels in brain parenchyma and cerebral amyloid angiopathy. Remarkably this was accompanied by abnormal HDL-like particle structure in the CSF and decreased levels of APOA-I and APOE. Thus, processes that regulate APOE expression and lipidation could affect its ability to influence brain homeostasis. In support of this hypothesis the lower level of APOE in carriers is associated with increased pathology and AD risk. Furthermore, stimulation of APOE expression and lipidation with LXR and RXR agonists is associated with reduced pathology and improved cognition in AD mouse models. The central hypothesis is that Abca1 affects formation/deposition and clearance, through lipidation of ApoE and formation of HDL, therefore therapeutic approaches which affect the levels of Abca1 and ApoE can be used to treat the pathology. To prove the hypothesis we use viral vectors to overexpress apolipoproteins and multiphoton microscopy to assess in vivo the effects on A¿ pathology and neuronal abnormalities in APP transgenic mice. Furthermore, we will characterize the effects of a clinically significant mutation of ABCA1 on APP mouse model phenotype. Lastly, we will examine how changes in peripheral and central expression of Abca1 affect lipid profiles and amyloid levels. The completion of this application will have a significant impact on our understanding of how different APOE alleles and a clinical relevant mutation of ABCA1 effects amyloid pathology. The design will allow for much more insight into a possible mechanism by which APOE affects AD progression. Furthermore, the application will further our understanding of the importance of central and peripheral ABCA1 in brain lipid profiles and amyloid levels, allowing for improved treatment targets. TRAINING IN THE RESPONSIBLE CONDUCT OF RESEARCH: Acceptable. The candidate has successfully completed training in the past and proposes additional focused training to supplement this background. The procedures for protection from research risks are satisfactory. Women and minorities are appropriately included in the research.

描述（由适用提供）：散发性阿尔茨海默氏病（AD）是一种未知病因的晚期痴呆，其特征是存在淀粉样蛋白B（A？），其中含有老年斑块，神经纤维纤维缠结和认知能力下降。重要的是，载脂蛋白（APOE）等位基因的遗传是零星发作AD的唯一既定风险因素。但是，这种关联的基础机制仍然难以捉摸。 ATP结合盒式转运蛋白A1（ABCA1）调节胆固醇从细胞到胆固醇受体的外排，主要脂肪脂化的载脂蛋白A-I A-I（APOA-I）和APOE产生新的高密度脂蛋白（HDL）。在表达小鼠的应用中，ABCA1的破坏增加了脑实质和脑淀粉样蛋白血管病中的斑块水平。值得注意的是，这是通过CSF中异常的HDL样粒子结构和提高APOA-I和APOE的水平来实现的。那是调节APOE表达和脂化的过程可能会影响其影响大脑体内平衡的能力。为了支持这一假设，载体中APOE的较低水平与病理增加和AD风险增加有关。此外，用LXR和RXR激动剂对APOE表达和脂化的模拟与AD小鼠模型中的病理减少和认知改善有关。中心假设是，ABCA1通过脂化和HDL的形成影响形成/沉积和清除，因此可以使用影响ABCA1和APOE水平的热方法来治疗病理。为了证明假设，我们使用病毒载体过表达载脂蛋白和多光子显微镜，以评估体内对APP转基因小鼠的病理和神经元异常的影响。此外，我们将表征ABCA1临床显着突变对App小鼠模型表型的影响。最后，我们将研究ABCA1的外周和中心表达的变化如何影响脂质谱和淀粉样蛋白水平。该应用程序的完成将对我们对不同APOE等位基因和ABCA1临床相关突变的理解产生重大影响。该设计将使您可以更深入地了解APOE影响AD进展的可能机制。此外，该应用将进一步了解中央和周围ABCA1在脑脂质谱和淀粉样蛋白水平中的重要性，从而改善治疗靶标。负责任的研究培训：可接受。候选人过去已经成功完成了培训，并提出了其他重点培训，以补充这种背景。保护风险的保护程序是满意厂。妇女和少数民族被适当地包括在研究中。