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: 10170195
• 负责人: Wellington Pham
• 金额: $ 71.67万
• 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/10170195
• 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; 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.

项目概要 该应用解决了检测早期出现的 β-淀粉样斑块的首要挑战 （Abeta）在阿尔茨海默病（AD）中的作用。它通过提出一种使用视网膜 Abeta 图像的新方法来实现这一点 姜黄素荧光 (FL) 发出的信号。 AD是老年人痴呆症的最常见原因 人们。其病理学特征是存在错误折叠和聚集的细胞外沉积物 Abeta 肽，随后从海马体扩散到大脑皮层，导致神经元 死亡并最终丧失记忆、逻辑和说话的能力。目前尚无疾病缓解疗法 无法有效对抗 AD，也不可能诊断疾病的早期发作和/或进展。 最近的研究结果表明，Abeta 蛋白水平升高与功能失调有关。 大脑和眼睛中的神经元网络。因为AD在发病前经历了一个漫长的无症状阶段 已达到晚期阶段，存在早期干预和成功检测的机会之窗 通过常规筛查来早期发现疾病将改善治疗效果并挽救生命。在那 就眼科中心而言，早期检测眼睛中的 Abeta 已广泛应用于各个健康领域 社区设置在实用性、可行性、安全性和成本方面似乎都很理想。 最近，我们的团队展示了一种通过吸入姜黄素在体内输送姜黄素的新方法 姜黄素气雾剂。此外，我们最近与 Joanne Matsubara 教授合作证明了 吸入姜黄素气雾剂会导致该化合物在视网膜中大量积聚。此外，我们还 证明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 可用作评估大脑中 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 作为 AD 的早期生物标志物。 一种不太成熟但潜在强大的方法，将药物化学与药物结合起来 递送和靶向分子成像是 AD 体内高灵敏度分子“指纹识别”的关键 这个高风险高回报提案的主题。