Biomarkers of ABCA1 mediated functions in Alzheimers disease

ABCA1 介导的阿尔茨海默病功能的生物标志物

• 批准号: 9289319
• 负责人: Hussein N Yassine
• 金额: $ 78.05万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9289319
• 关键词: ATP binding cassette transporter 1; Activities of Daily Living; Age; Aging; Agonist; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid deposition; Apolipoprotein E; Bexarotene; Biological Markers; Brain; Cells; Cerebrospinal Fluid; Cholesterol; Clinical Research; Clinical Trials; Cognition; Cognitive; Data; Diabetes Mellitus; Drug usage; Dyslipidemias; Elderly; Functional disorder; Generations; Genes; Genotype; Goals; Grant; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Impaired cognition; Intervention; Label; Lipids; Lipoproteins; Mediating; Memory Loss; Metabolism; Outcome; Participant; Pathway interactions; Peptides; Peripheral; Phospholipids; Population; Positron-Emission Tomography; Proteins; Recruitment Activity; Reporting; Research; Research Infrastructure; Risk Factors; Sampling; Senile Plaques; Serum; Suggestion; Therapeutic; Work; apolipoprotein E-4; base; brain cell; cerebral amyloidosis; cognitive function; diabetic; follow-up; improved; indexing; lipid metabolism; lipid transport; loss of function mutation; mild cognitive impairment; mouse model; novel marker; novel strategies; particle; peptidomimetics; personalized medicine; predictive marker; rosiglitazone; specific biomarkers

Carrying the ApoE ε4 allele and low HDL cholesterol diabetic dyslipidemia are risk factors of Alzheimer’s disease (AD). How low HDL cholesterol levels or ApoE4 HDL proteins increase AD risk is far from being completely understood. The efflux of cholesterol and lipids to ApoE-containing lipoproteins is the first step in the formation of brain HDL. ABCA1 is a major transporter of lipids to ApoE-containing lipoproteins. In AD mouse models, the absence of the ABCA1 gene decreases brain HDL and increases brain amyloid deposition. Conversely, facilitating ABCA1 lipid transport decreases amyloid plaques and improves cognition. In humans, loss-of-function mutations in the ABCA1 gene are associated with increased AD risk. Therefore, targeting ABCA1 is a promising therapeutic strategy in AD. One promising therapy is the ApoE mimetic peptide “CS- 6253”. CS-6253 enhances the rate of ABCA1-driven efflux of cholesterol and phospholipids from cells to form HDL. Using a novel approach, we examined the capacity of cerebrospinal fluid (CSF) to transport cholesterol from cells expressing the ABCA1 transporter and demonstrated significantly reduced ABCA1 mediated cholesterol efflux capacity in participants with mild cognitive impairment and AD compared to healthy controls. Our preliminary data reveal decreased cholesterol efflux capacity in cognitively healthy older ApoE ε4 carriers compared to non-carriers. We hypothesize that this functional capacity of CSF can serve as a biomarker providing unique information regarding pathophysiology of AD and identifying participants that could be benefit from ABCA1 agonist treatments. In this project, we propose to (1) determine the effect of the ApoE mimetic peptide “CS-6253” on the capacity of CSF to efflux cholesterol and lipids out of ABCA1 expressing cells and ApoE lipidation ex vivo, (2) determine ABCA1 mediated cholesterol efflux capacity and ApoE lipidome composition of HDL from existing 107 CSF and serum samples obtained of cognitively healthy older participants, and (3) determine whether ABCA1 mediated cholesterol efflux capacity of CSF and serum HDL is associated with rapid memory decline after 4 years of longitudinal follow-up. This project will take advantage of the clinical research infrastructure and existing samples afforded to us by the USC Alzheimer’s Disease Research Center. Achieving our aim will identify ABCA1 mediated cholesterol efflux capacity as a novel biomarker in AD and a potential target for personalized AD interventions.

携带APOEε4等位基因和低HDL胆固醇糖尿病血脂异常是阿尔茨海默氏症的危险因素 疾病（AD）。 HDL胆固醇水平或APOE4 HDL蛋白增加AD风险的程度远非如此 完全理解。胆固醇和脂质对含APOE的脂蛋白的外排是第一步 脑HDL的形成。 ABCA1是脂质到含APOE的脂蛋白的主要转运蛋白。在广告中 小鼠模型，不存在ABCA1基因会降低脑HDL并增加脑淀粉样蛋白沉积。 相反，促进ABCA1脂质转运可减少淀粉样斑块并改善认知。在人类中 ABCA1基因的功能丧失突变与AD风险增加有关。因此，定位 ABCA1是AD的一种有希望的疗法。一种有希望的疗法是ApoE模拟肽“ CS- 6253“。CS-6253提高了ABCA1驱动的胆固醇和磷脂从细胞形成的速率 HDL。我们使用一种新的方法检查了脑脊液（CSF）运输胆固醇的能力 通过表达ABCA1转运蛋白的细胞并显示出显着降低的ABCA1介导的 与健康对照组相比，患有轻度认知障碍和AD的参与者的胆固醇外排能力。 我们的初步数据显示，认知健康的老年APOEε4载体的胆固醇能力提高了 与非携带者相比。我们假设CSF的这种功能能力可以用作生物标志物 提供有关AD病理生理学的独特信息，并确定可能受益的参与者 来自ABCA1激动剂治疗。在这个项目中，我们建议（1）确定apoe模拟的效果 肽“ CS-6253”关于CSF对ABCA1表达细胞的能力和脂质的能力 ApoE脂质离体，（2）确定ABCA1介导的胆固醇外排和APOE脂肪姆 来自现有的107 CSF和血清样品的HDL成分 参与者和（3）确定ABCA1介导的CSF和血清HDL的胆固醇外排能力是 在4年的纵向随访后，记忆力下降与快速记忆有关。这个项目将利用 南加州大学阿尔茨海默氏病为我们提供的临床研究基础设施和现有样本 研究中心。实现我们的目标将识别ABCA1介导的胆固醇外排作为一种新颖 AD中的生物标志物，也是个性化广告干预措施的潜在目标。