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.

携带载脂蛋白Eε4等位基因和低高密度脂蛋白糖尿病血脂异常是阿尔茨海默病的危险因素 疾病(AD)。低密度脂蛋白胆固醇水平或ApoE4高密度脂蛋白如何增加阿尔茨海默病风险还远未确定 完全理解。胆固醇和脂类外流到含ApoE的脂蛋白是 脑内高密度脂蛋白的形成。ABCA1是脂类向含ApoE的脂蛋白的主要转运体。在AD中 在小鼠模型中，ABCA1基因的缺失降低了大脑的高密度脂蛋白，增加了大脑淀粉样蛋白的沉积。 相反，促进ABCA1的脂质运输可以减少淀粉样斑块并改善认知。在人类身上， ABCA1基因功能丧失突变与AD风险增加相关。因此，目标是 ABCA1是一种很有前途的AD治疗策略。一种很有希望的治疗方法是ApoE模拟肽“CS- 6253“。CS-6253提高ABCA1驱动的胆固醇和磷脂从细胞外流形成的速度 高密度脂蛋白。使用一种新的方法，我们检测了脑脊液(Csf)运输胆固醇的能力。 从表达ABCA1转运蛋白的细胞中分离出来，并显示ABCA1介导的显著减少 轻度认知障碍和阿尔茨海默病患者的胆固醇流出能力与健康对照组相比。 我们的初步数据显示，认知健康的老年载脂蛋白Eε4携带者胆固醇外流能力降低 与非携带者相比。我们假设脑脊液的这种功能能力可以作为一个生物标志物。 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激动剂的治疗。在这个项目中，我们建议(1)确定载脂蛋白E模拟物的效果 CS-6253肽对脑脊液将胆固醇和脂类从ABCA1表达细胞中排出的影响 载脂蛋白E体外脂化；(2)ABCA1介导的胆固醇流出能力和载脂蛋白E脂质体的测定 107例认知健康老年人脑脊液和血清标本的高密度脂蛋白组成 以及(3)确定ABCA1介导的脑脊液胆固醇流出能力和血清高密度脂蛋白是否 与4年纵向随访后记忆力快速下降有关。这个项目将利用 南加州大学阿尔茨海默病向我们提供的临床研究基础设施和现有样本 研究中心。实现我们的目标将确认ABCA1介导的胆固醇外流能力是一种新的 AD中的生物标记物和个性化AD干预的潜在靶点。