Validation of Retinal Abeta as a Potential Biomarker of Alzheimer's Disease

验证视网膜 Abeta 作为阿尔茨海默病的潜在生物标志物

• 批准号: 10431819
• 负责人: Wellington Pham
• 金额: $ 69.85万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431819
• 关键词: Address; Aerosols; Affinity; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer’s disease biomarker; Amyloid beta-Protein; Binding; Biodistribution; Biological Assay; Blood; Brain; Cerebral cortex; Cessation of life; Chemicals; Collaborations; Community Health; Curcumin; Data; Dementia; Deposition; Detection; Disease; Disease Progression; Dose; Drug Delivery Systems; Early Diagnosis; Early Intervention; Elderly; Excretory function; Eye; Fluorescence; Formulation; Foundations; Goals; Hippocampus (Brain); Image; Inhalation; Kinetics; Lead; Logic; Memory Loss; Metabolism; Methods; Modification; Molecular Profiling; Molecular Target; Monitor; Mus; Nerve Degeneration; Neurons; Onset of illness; Ophthalmology; Pathology; Patients; Peptides; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Proteins; Reporting; Reproducibility; Retina; Safety; Senile Plaques; Signal Transduction; Specificity; Surrogate Markers; Technology; Testing; Time; Tissues; Toxic effect; Validation; Work; absorption; aerosolized; analog; base; chemical genetics; cohort; community setting; cost; early detection biomarkers; early onset; extracellular; functional group; high reward; high risk; improved; in vivo; in vivo evaluation; in vivo imaging; microscopic imaging; molecular imaging; neuron loss; novel; novel strategies; potential biomarker; professor; response; retinal imaging; routine screening; screening; therapy outcome; tool

PROJECT SUMMARY This application addresses the overarching challenge of detection of the early onset of β-amyloid plaques (Abeta) in Alzheimer's disease (AD). It does so by proposing a novel approach to image retinal Abeta by using signals emitted by curcumin fluorescence (FL). AD is the most common cause of dementia among elderly people. Its pathology is characterized by the presence of extracellular deposits of misfolded and aggregated Abeta peptides, which subsequently spread from the hippocampus to the cerebral cortex causing neuronal death and ultimately loss of memory, logic and the ability to speak. At present, no disease-modifying therapy is effective against AD nor it is possible to diagnose the early onset and/or the progress of the disease. Recent findings indicate that elevated levels of Abeta proteins are associated with dysfunctional neuronal networks both in the brain and eyes. Because AD undergoes a protracted asymptomatic stage before it reaches the advanced stage, a window of opportunity exists for early intervention, and successful detection of the early onset of the disease via routine screening will improve therapeutic outcomes and save lives. In that regard, early detection of Abeta in the eyes at ophthalmology centers, widely available in every health community settings seems ideal in terms of practicality, feasibility, safety and cost. Recently, our group demonstrated a novel approach for delivery of curcumin in vivo via inhalation of the curcumin aerosol. Further, in collaboration with Professor Joanne Matsubara, we recently demonstrated that inhaling curcumin aerosol resulted in significant accumulation of the compound in the retina. Further, we also demonstrated that curcumin binds to Abeta in retinal sublayers. Building on that foundation, we hypothesize that curcumin FL in the eyes can be used as a surrogate biomarker for assessing Abeta levels in the brain. Our long-term objective is to (i) demonstrate the newly synthesized curcumin analogs can be distributed and bind effectively to retinal Abeta; (ii) demonstrate retinal Abeta as a early biomarker of AD. A less well developed, but potentially powerful approach, marrying medicinal chemistry with drug delivery, and targeted molecular imaging, for high sensitivity molecular “fingerprinting” of AD in vivo, is the subject of this high risk-high reward proposal.

项目总结 这项应用解决了检测β-淀粉样斑块早期发病的主要挑战 (Abeta)在阿尔茨海默病(AD)中。为此，它提出了一种新的方法来成像视网膜Abeta，通过使用 姜黄素荧光(FL)发出的信号。AD是老年人痴呆症最常见的原因 人民。其病理特征是存在错误折叠和聚集的细胞外沉积。 Abeta多肽，随后从海马区扩散到大脑皮层，导致神经元 死亡，最终失去记忆、逻辑和说话能力。目前，还没有一种疾病修正疗法是 对阿尔茨海默病有效，也不可能诊断疾病的早期发病和/或进展。 最近的发现表明，Abeta蛋白水平的升高与功能障碍有关 大脑和眼睛中的神经元网络。因为AD在之前经历了一个旷日持久的无症状阶段 到了晚期，存在早期干预和成功检测的机会之窗 通过常规筛查及早发现该病将改善治疗结果并挽救生命。在那 关于，眼科中心的眼睛中早期检测到Abeta，在每个健康人中都可以广泛获得 社区环境在实用性、可行性、安全性和成本方面似乎都很理想。 最近，我们小组展示了一种通过吸入姜黄素体内给药的新方法。 姜黄素气雾剂。此外，在与Joanne Matsubara教授的合作下，我们最近证明了 吸入姜黄素气雾剂会导致这种化合物在视网膜中显著积聚。此外，我们还 证明了姜黄素与视网膜亚层中的Abeta结合。在此基础上，我们假设 眼睛中的姜黄素FL可以作为评估大脑中Abeta水平的替代生物标志物。我们的 长期目标是(I)证明新合成的姜黄素类似物可以分布和结合 对视网膜Abeta有效；(Ii)证明视网膜Abeta是AD的早期生物标志物。 一种不太成熟，但潜在的有效方法，将药物化学与药物结合起来 传递和靶向分子成像，用于在活体内对AD进行高灵敏度的分子指纹识别，是 这项高风险-高回报建议的主题。