Peripheral & Brain Cholesterol Metabolism in Neurodegenerative Mouse Models

周边

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' 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

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）是一种病因不明的晚发性痴呆，其特征是存在含有老年斑、神经原纤维缠结和认知能力下降的β淀粉样蛋白（a β）。重要的是，载脂蛋白（APOE）等位基因的遗传是唯一确定的散发性晚发型AD的危险因素。然而，这种关联背后的机制仍然难以捉摸。ATP结合盒转运蛋白A1 （ABCA1）调节胆固醇从细胞向胆固醇受体的外排，主要是低脂载脂蛋白A-I （APOA-I）和APOE，从而产生新生的高密度脂蛋白（HDL）。在表达APP的小鼠中，Abca1的破坏增加了脑实质斑块水平和脑淀粉样血管病。值得注意的是，这伴有脑脊液中高密度脂蛋白样颗粒结构异常和APOA-I和APOE水平下降。因此，调节APOE表达和脂化的过程可能影响其影响脑Aβ稳态的能力。为了支持这一假设，携带者中较低水平的APOE与Aβ病理和AD风险增加有关。此外，LXR和RXR激动剂刺激APOE表达和脂化与AD小鼠模型的病理减轻和认知改善有关。核心假设是Abca1通过ApoE的脂化和HDL的形成影响Aβ的形成/沉积和清除，因此影响Abca1和ApoE水平的治疗方法可用于治疗Aβ病理。为了证明这一假设，我们利用病毒载体过表达载脂蛋白和多光子显微镜观察了APP转基因小鼠体内对Aβ病理和神经元异常的影响。此外，我们将描述ABCA1临床显著突变对APP小鼠模型表型的影响。最后，我们将研究Abca1外周和中枢表达的变化如何影响脂质谱和淀粉样蛋白水平。这项应用的完成将对我们理解不同的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产生重大影响。该设计将允许更深入地了解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的重要性的理解，从而改善治疗靶点。