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

项目摘要 该应用解决了检测β-淀粉样蛋白斑块早期发作的首要挑战 （Abeta）在阿尔茨海默病（AD）中。它通过提出一种新的方法来成像视网膜Abeta， 由姜黄素荧光（FL）发射的信号。AD是老年痴呆症的最常见原因 人其病理学特征是存在错误折叠和聚集的细胞外沉积物。 Abeta肽随后从海马扩散到大脑皮质，引起神经元损伤 死亡并最终丧失记忆、逻辑和说话能力。目前，没有疾病修饰疗法是有效的。 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障碍有关。 大脑和眼睛的神经网络。因为AD在发病前经历了一个漫长的无症状阶段， 它达到了晚期，存在早期干预和成功检测的机会窗口 通过常规筛查来预防疾病的早期发作将改善治疗结果并挽救生命。在这 在这方面，在眼科中心早期发现眼睛中的Abeta，在每个健康中心都可以广泛使用， 从实用性、可行性、安全性和成本来看，社区环境似乎是理想的。 最近，我们的小组展示了一种通过吸入姜黄素在体内递送姜黄素的新方法。 姜黄素气雾剂此外，在与Joanne Matsubara教授的合作中，我们最近证明， 吸入姜黄素气雾剂导致该化合物在视网膜中显著积累。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可以用作评估大脑中Abeta水平的替代生物标志物。我们 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 有效地抑制视网膜A β;（ii）证明视网膜A β是AD早期生物标志物。 一种不太发达但潜在强大的方法，将药物化学与药物结合起来， 递送和靶向分子成像，用于体内AD的高灵敏度分子"指纹"，是 这个高风险高回报的提议的主题

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.