Biomarkers of ABCA1 mediated functions in Alzheimers disease

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 疾病（AD）。低HDL胆固醇水平或ApoE 4 HDL蛋白如何增加AD风险还远未被证实。 完全理解胆固醇和脂质向含ApoE的脂蛋白的流出是 大脑HDL的形成。ABCA 1是脂质向含ApoE的脂蛋白的主要转运蛋白。AD中 在小鼠模型中，ABCA 1基因的缺失降低了脑HDL并增加了脑淀粉样蛋白沉积。 相反，促进ABCA 1脂质转运减少淀粉样斑块，改善认知。在人类中， ABCA 1基因的功能缺失突变与AD风险增加相关。因此，针对 ABCA 1是AD的一种有前途的治疗策略。一种有前景的疗法是ApoE模拟肽“CS-1”。 6253”。CS-6253增强ABCA 1驱动的胆固醇和磷脂从细胞中流出的速率， HDL。使用一种新的方法，我们研究了脑脊液（CSF）转运胆固醇的能力 从表达ABCA 1转运蛋白的细胞中， 与健康对照组相比，轻度认知障碍和AD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携带者胆固醇流出能力降低 与非运营商相比。我们假设CSF的这种功能性可以作为生物标志物 提供关于AD病理生理学的独特信息，并确定可能受益的参与者 ABCA 1激动剂治疗。在这个项目中，我们建议（1）确定ApoE模拟物的作用 肽“CS-6253”对CSF将胆固醇和脂质流出表达ABCA 1的细胞的能力的影响， ApoE离体脂质化，（2）测定ABCA 1介导的胆固醇流出能力和ApoE脂质体 从认知健康老年人获得的现有107份CSF和血清样本中的HDL组成 参与者，和（3）确定是否ABCA 1介导的CSF和血清HDL的胆固醇流出能力， 与4年纵向随访后记忆力快速下降相关。该项目将利用 南加州大学阿尔茨海默病研究所提供给我们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ABCA 1介导的胆固醇流出能力作为一种新的 AD中的生物标志物和个性化AD干预的潜在靶点。

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.