Novel Specific Ligands for ABeta Oligomers

描述（由申请人提供）：该项目旨在开发一类新的分子，这些分子与被认为导致阿尔茨海默病（AD）的淀粉样蛋白(a)的神经毒性形式具有特异性和高亲和力。到目前为止，阿尔茨海默病还没有治愈的方法，目前的治疗只能使症状得到中度和暂时的缓解。阿尔茨海默病的临床诊断灵敏度约为85%，而明确的诊断只有在尸检后才能得到。阿尔茨海默病的有效诊断和治疗可能需要敏感和特异性的工具来早期发现，并干预导致阿尔茨海默病发展的神经毒性过程。

DESCRIPTION (provided by applicant): This project aims to develop a novel class of molecules that interact specifically and with high affinity with neurotoxic forms of amyloid ¿-protein (A¿), which are believed to cause Alzheimer's disease (AD). To date, AD has no cure and current treatments yield only moderate and temporary relief of symptoms. The clinical diagnosis of AD has sensitivity of ~85%, whereas a definite diagnosis is achieved only post mortem. Effective diagnosis and treatment for AD likely will require sensitive and specific tools for early detection of, and intervention against the neurotoxic processes that lead to development of AD. The new molecules, termed aptamers, will be selected from a library of 10(15) DNA sequences using well established methods that have been shown to yield ligands with high affinity and specificity for a large variety of targets. A difficult problem in the AD field is that the relevant targets are metastable assemblies of A¿, which are difficult to study and isolate. We will overcome this difficulty employing a photochemical cross-linking technique previously developed in our laboratory to stabilize these assemblies. This method enables quantitative purification of individual assemblies. The project includes the following steps: First, aptamers with high affinity and high specificity for neurotoxic A¿ assemblies will be generated. Second, we will develop an aptamer-based diagnostic technique and will use this technique to analyze cerebrospinal fluid samples from patients with AD and from healthy individuals. Third, we will assess the capability of the aptamers to inhibit the neurotoxic effect of A¿ in cultures of neuronal cells as a first step towards development of aptamer-based drugs for treatment of AD. Using this systematic approach, we expect to obtain aptamers with high affinity and high specificity for the metastable, neurotoxic A¿ assemblies and to use these aptamers as novel, mechanism-based tools for AD diagnostics and therapeutics.