A major reason for failure of a biomarker to act as true disease surrogate endpoint is the lack of a direct association between the biomarker and the underlying mechanism of the disease. Fibrillar beta-amyloid (AB) plaques are the main pathological hallmark of Alzheimer's disease (AD), although its role as a causative mechanism in AD is controversial and continues to be disputed. The clear association of soluble AB oligomers to neurotoxicity in animal studies indicates that measuring soluble AB oligomers may hold more promise as a true surrogate biomarker for the clinical symptoms of AD. The lack of specific ligands that can differentiate soluble AB oligomers from fibrillar AB forms both in vitro and in vivo has hindered studies aimed at testing the correlation between soluble AB oligomers and plaques and/or the relative clinical value of measuring different forms of AB species. Our group discovered a fluorophore, 68B-3, that can selectively bind soluble AB oligomers and has no measurable binding to AB fibrils or monomers. The primary aims of this study are to characterize and validate our initial discovery on 68B-3, and evaluate the value of measuring different forms of AB species in clinical samples and in a transgenic model of AD. We will determine the correlation between levels and location of soluble AB oligomers to disease progression. While the affinity of 68B-3 to synthetic soluble AB oligomers is low, it may serve as a useful tool in providing novel information in biological samples. Furthermore, it may be optimized by chemistry to yield derivatives with better properties. Another aim of this study is to understand the mechanism of binding of 68B-3 to soluble AB oligomers. This is an important first step to improving its binding affinity. It is our intent to make 68B-3 available to researchers once we have validated its uses and once we have demonstrated the robustness of our preliminary data. Selective small molecule probes such as 68B-3 will not only serve as potential tracers for non-invasive imaging, but may be used in ex vivo postmortem studies to compare the regional distribution and temporal profile of soluble AB oligomers and plaques. Such information would enable the correlation of neuronal loss with the spatial location of soluble AB oligomers and thus may accelerate the establishment of a true surrogate for the diagnosis of early AD.
The proposed research is directed toward the validation of our initial discovery using 68B-3, a novel small molecule fluorophore that selectively targets soluble beta-amyloid (AB) oligomers and not fibrils or monomers, and evaluation of the value of measuring different forms of AB species. Completion of this study will be important to investigate the regional distribution and temporal kinetics of soluble AB oligomers compared to fibrillar AB in postmortem tissues and animal models of Alzheimer's disease. This would also provide powerful insight into understanding the role of soluble AB oligomers in the pathogenesis of Alzheimer's disease and the clinical value of measuring levels of soluble AB oligomers.
