Biomarker for Alzheimer's Related Cognitive Deficits

描述(由申请人提供)：阿尔茨海默病(AD)潜在的分子和细胞细节正在加速确定，导致新的治疗发现努力，目标是减少A-β或ADDL(A-β衍生的可扩散配体)，A-β1-42的神经毒性寡聚体组装。ADTL水平升高与突触功能障碍相关，在转基因AD动物模型Tg2576 AD小鼠中，脑组织中ADDLS的出现与认知能力下降相一致。最近的研究表明，ADDLS在AD脑组织中升高了70倍，而且ADDLS直接干扰突触功能、学习和记忆。即使血清样本中的ADDLS水平很低，也可能预示着认知能力的下降。这项提议旨在开发能够测量人体体液和组织样本中ADTL水平的诊断测试。这样的测试将有助于在ADTL水平和认知缺陷之间建立联系。血清或脑脊液(CSF)的ADTL诊断将是识别AD和轻度认知障碍(MCI)相关患者作为临床试验参与者的有价值的工具。对于降低Abeta或ADDL水平的药物的测试，ADDL的定量诊断将是确定症状疗效与ADDR水平下降平行的关键。Acumen及其合作者已经开发出基于ELISA的灵敏技术，可以检测人类脑脊液样本中毫微摩尔水平的ADDLS。对ADTL选择性抗体的实验提供了初步证据，表明Tg2576小鼠和唐氏综合症患者的血浆样本中存在ADDLS。这些令人鼓舞的初步数据为这项建议奠定了基础：1)优化ADTL检测能力，2)优化适合作为人类临床样本参考测试的ADTL诊断分析格式，3)验证ADTL水平与人类认知缺陷相关的假设。目标一和目标二将是第一阶段的重点，目标三将是第二阶段的重点。

DESCRIPTION (provided by applicant): The molecular and cellular details underlying Alzheimer's disease (AD) are being defined at an accelerating pace, leading to new therapeutic discovery efforts that target reduction of A-beta or ADDLs (A-beta-derived diffusible ligands), the neurotoxic oligomeric assemblies of A-beta 1-42. Elevated ADDL levels correlate with synaptic dysfunction, and the appearance of ADDLs in brain tissue coincides with cognitive decline in Tg2576 AD mice, a transgenic AD animal model. Recent studies have demonstrated that ADDLs are 70-fold elevated in AD brain tissue, and that ADDLs interfere directly with synaptic function, learning and memory. It is possible that even low levels of ADDLs in serum samples may predict cognitive decline. This proposal aims to develop diagnostic tests that can measure ADDL levels in human fluid and tissue samples. Such tests will help establish a connection between ADDL levels and cognitive deficits. A serum or cerebrospinal fluid (CSF) ADDL diagnostic will be a valuable tool for identification of relevant patients with AD and mild cognitive impairment (MCI) as clinical trial participants. For testing of drugs that lower Abeta or ADDL levels, a quantitative ADDL diagnostic will be pivotal to establish that symptomatic efficacy parallels a drop in ADDL levels. Acumen and its collaborators have developed sensitive ELISA-based technology that detects ADDLs at femtomolar levels in human CSF samples. Experiments with ADDL-selective antibodies have provided preliminary evidence that ADDLs are present in plasma samples from Tg2576 mice and Down's syndrome patients. These encouraging preliminary data serve as the foundation for this proposal to: 1) optimize ADDL detection capabilities, 2) optimize an ADDL diagnostic assay format suitable as a reference test for human clinical samples, and 3) validate the hypothesis that ADDL levels correlate with human cognitive deficits. Objectives one and two will be the focus of Phase I, and objective three will be the focus of Phase II.