Peripheral & Brain Cholesterol Metabolism in Neurodegenerative Mouse Models

周边

基本信息

批准号：
9249458
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/9249458
关键词：
ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Abeta clearance Abeta synthesis Adenovirus Vector Affect Age Agonist Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Apolipoprotein A-I Apolipoprotein E Apolipoproteins Astrocytes Binding Blood Vessels Brain Brain Diseases Brain imaging Cells Cerebral Amyloid Angiopathy Cholesterol Cholesterol Homeostasis Cognition Complex Dementia Deposition Disease Progression Etiology Excision Genetic High Density Lipoproteins Homeostasis Human Immunization Impaired cognition Impairment In Vitro Knock-in Mouse Knock-out Knockout Mice Label Late Onset Alzheimer Disease Learning Link Lipids Lipoproteins Liver Liver X Receptor Mediating Membrane Microglia Microscopy Molecular Chaperones Mus Mutation Nerve Degeneration Neurofibrillary Tangles Neurons Pathologic Pathology Patients Peripheral Phenotype Predisposition Process Proteins RXR Risk Factors Role Route Senile Plaques Serum Severity of illness Structure Techniques Therapeutic Time Tissues Toxic effect Transgenic Mice Up-Regulation Viral Vector abeta accumulation abeta deposition amyloid pathology amyloid precursor protein processing apolipoprotein E-4 base beta amyloid pathology brain parenchyma clinically relevant clinically significant design genetic risk factor high risk improved in vivo insight lipid I mouse model multiphoton imaging neuropathology overexpression particle public health relevance receptor trafficking

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 β (Aβ) 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 Aβ homeostasis. In support of this hypothesis the lower level of APOE in carriers is associated with increased Aβ 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 Aβ 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 Aβ pathology. To prove the hypothesis we use viral vectors to overexpress apolipoproteins and multiphoton microscopy to assess in vivo the effects on Aβ 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.

描述（由申请人提供）：散发性阿尔茨海默病（AD）是一种病因不明的迟发性痴呆，其特征是存在含有老年斑的β淀粉样蛋白（Aβ）、神经原纤维缠结和认知能力下降，重要的是，载脂蛋白的遗传。 (APOE) 等位基因是散发性迟发性 AD 的唯一确定的危险因素，然而，这种关联的机制仍然难以捉摸。盒式转运蛋白 A1 (ABCA1) 调节胆固醇从细胞流出至胆固醇受体，主要是低脂化载脂蛋白 A-I (APOA-I) 和 APOE，从而产生新生高密度脂蛋白 (HDL)。表达 APP 的小鼠中 Abca1 的破坏增加了脑实质中的斑块水平。值得注意的是，这还伴随着脑脊液中 HDL 样颗粒结构的异常以及 APOA-I 和 APOA-I 水平的降低。因此，调节 APOE 表达和脂化的过程可能会影响其影响大脑 Aβ 稳态的能力，支持这一假设，携带者中 APOE 水平较低与 Aβ 病理学和 AD 风险增加有关。 LXR 和 RXR 激动剂的脂化与 AD 小鼠模型中病理的减少和认知的改善有关。中心假设是 Abca1 通过 ApoE 的脂化和 ApoE 的形成影响 Aβ 的形成/沉积和清除。 HDL，因此影响 Abca1 和 ApoE 水平的治疗方法可用于治疗 Aβ 病理学。为了证明这一假设，我们使用病毒载体过表达载脂蛋白和多光子显微镜来评估体内对 Aβ 病理学和 APP 神经元异常的影响。此外，我们将描述具有临床意义的 ABCA1 突变对 APP 小鼠模型表型的影响。最后，我们将研究 Abca1 的外周和中枢表达的变化如何影响脂质谱。该应用的完成将对我们了解不同的 APOE 等位基因和 ABCA1 的临床相关突变如何影响淀粉样蛋白病理学产生重大影响。该设计将使我们能够更深入地了解 APOE 影响 AD 的可能机制。此外，该应用将进一步加深我们对中枢和外周 ABCA1 在脑脂质谱和淀粉样蛋白水平中重要性的理解，从而改善治疗目标。