Development of selective amyloid-responsive fluorescent probes

项目摘要 淀粉样蛋白在大脑中的堆积是阿尔茨海默病(AD)和许多其他相关疾病的普遍特征 痴呆症，比临床症状早几年。淀粉样蛋白的生前检测方法 因此，物种可能有助于诊断和监测神经退行性变，提供关键信息 可用于为患者管理制定适当的计划。虽然一些临床工具用于检测 大脑或脑脊液中的淀粉样蛋白已经被开发出来，以帮助诊断阿尔茨海默病，区分 AD来源于非AD患者的神经病理活体是有限的。我们最近开发了两个新的家族 荧光探针可以选择性地检测tau或α-突触核蛋白的聚集形式，这可能会解决 通过扩展用于帮助检测淀粉样蛋白或淀粉样聚集体的现有工具箱来满足未满足的需求 与非AD疾病相关，如额颞性痴呆(FTD)、帕金森病(PD)和其他 神经官能症和联核病。拟议中的研究试图发现新的可靠的设计原则 开发这种选择性的淀粉样蛋白反应探针，并将寻求评估其在检测 用于生前诊断的新兴平台中的淀粉样蛋白种类。这项建议的具体目的是： 1)开发荧光探针，该荧光探针在结合到聚集体上时表现出选择性的荧光增强 α-突触核蛋白或tau与ABeta在溶液和组织中的比较；2)建立一种方法来表征 生物体液中淀粉样蛋白的聚集；以及3)评估选择性淀粉样蛋白反应 荧光探针可以用来对视网膜中特定的淀粉样沉积进行成像。

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.