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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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 ApoE ε4 等位基因和低 HDL 胆固醇糖尿病血脂异常是阿尔茨海默病的危险因素低 HDL 胆固醇水平或 ApoE4 HDL 蛋白会增加 AD 风险的程度还远未可知。胆固醇和脂质流向含有 ApoE 的脂蛋白是第一步。 AD 中 HDL 的形成是脂质向含有 ApoE 的脂蛋白的主要转运蛋白。在小鼠模型中，ABCA1 基因的缺失会降低大脑高密度脂蛋白并增加大脑淀粉样蛋白沉积。离线时，促进 ABCA1 脂质运输可减少淀粉样斑块并改善人类的认知能力。 ABCA1 基因的功能丧失突变与 AD 风险增加相关，因此，靶向治疗。 ABCA1 是 AD 的一种有前途的治疗策略，其中一种有前途的疗法是 ApoE 模拟肽“CS-”。 6253”，CS-6253 增强了 ABCA1 驱动的胆固醇和磷脂从细胞中流出的速率。 HDL。我们使用一种新方法检查了脑脊液 (CSF) 转运胆固醇的能力。来自表达 ABCA1 转运蛋白的细胞，并证明 ABCA1 介导的显着降低与健康对照相比，患有轻度认知障碍和 AD 的参与者的胆固醇流出能力。我们的初步数据显示认知健康的老年 ApoE ε4 携带者的胆固醇流出能力降低与非携带者相比，我们勇敢地认为脑脊液的这种功能能力可以作为生物标志物。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在该项目中，我们建议 (1) 确定 ApoE 模拟物的效果。肽“CS-6253”对脑脊液从 ABCA1 表达细胞中流出胆固醇和脂质的能力的影响离体 ApoE 脂质化，(2) 测定 ABCA1 介导的胆固醇流出能力和 ApoE 脂质组来自认知健康老年人的现有 107 个脑脊液和血清样本中的 HDL 成分参与者，(3) 确定 ABCA1 介导的 CSF 和血清 HDL 胆固醇流出能力是否该项目将利用 4 年纵向随访后与记忆力快速衰退相关的情况。南加州大学阿尔茨海默病中心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定 ABCA1 介导的胆固醇流出能力作为一种新的能力。 AD 的生物标志物和个性化 AD 干预的潜在目标。