Development of selective amyloid-responsive fluorescent probes

项目摘要 脑中淀粉样蛋白积聚是阿尔茨海默病（AD）和许多其他相关疾病的普遍特征。 痴呆症和临床症状之前几年。淀粉样蛋白的生前检测方法 因此，物种可以帮助诊断和监测神经变性，提供关键信息， 可以用来设计一个适当的计划，病人管理。虽然许多临床工具用于检测 已经开发了脑或脑脊液中的淀粉样蛋白来帮助诊断AD， AD与非AD神经病理学在存活患者中的区别有限。我们最近开发了两个新的家庭， 可以选择性地检测tau或α-突触核蛋白的聚集形式的荧光探针， 通过扩展可用工具箱来帮助检测淀粉样蛋白或淀粉样蛋白样聚集体， 与非AD疾病如额颞叶痴呆（FTD）、帕金森病（PD）和其他 tau蛋白病和共核蛋白病。拟议的研究旨在揭示新的和可靠的设计原则 用于开发这种选择性淀粉样蛋白响应探针，并将寻求评估它们用于检测 淀粉样蛋白物种在新兴平台的死前诊断。该提案的具体目标是： 1)开发荧光探针，其在与聚集的 a-突触核蛋白或tau与溶液和组织中的ABeta; 2）开发表征α-突触核蛋白或tau的分布的方法， 生物流体中淀粉样蛋白生成蛋白的聚集体;以及3）评估选择性淀粉样蛋白响应性聚合物是否与生物流体中的淀粉样蛋白生成蛋白的聚集体相关。 荧光探针可用于成像视网膜中的特定淀粉样蛋白沉积物。

Project Summary Amyloid accumulation in the brain is a universal feature of Alzheimer’s disease (AD) and many other related dementias and precedes clinical symptoms by several years. Methods for antemortem detection of amyloid species may, therefore, aid in diagnosing and monitoring neurodegeneration, providing critical information that can be used to devise a proper plan for patient management. While a number of clinical tools for detecting amyloid in the brain or cerebral spinal fluid have been developed to help diagnose AD, methods to differentiate AD from non-AD neuropathology in living patients are limited. We have recently developed two new families of fluorescent probes that can selectively detect aggregated forms of tau or alpha-synuclein, which could address an unmet need by extending the available toolbox for aiding in detection of amyloid or amyloid-like aggregates associated with non-AD diseases such as Frontotemporal Dementia (FTD), Parkinson’s disease (PD), and other tauopathies and synucleinopathies. The proposed research seeks to uncover new and reliable design principles for developing such selective amyloid-responsive probes and will seek to evaluate their utility for detection of amyloid species in emerging platforms for antemortem diagnostics. The Specific Aims of this proposal are to: 1) Develop fluorescent probes that exhibit selective enhancement of fluorescence upon binding to aggregated alpha-synuclein or tau versus ABeta in solution and in tissue; 2) Develop a method to characterize the distribution of aggregates of amyloidogenic proteins in biofluids; and 3) Evaluate whether selective amyloid-responsive fluorescent probes can be used to image specific amyloid deposits in the retina.