Beta-Amyloid Degradation in CSF as a Biomarker for Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征在于淀粉样蛋白b-蛋白（Ab）在影响记忆和认知的脑区域中的异常积累。新出现的证据表明，抗体的蛋白水解降解的缺陷可能有助于一个相当大的比例的特发性AD病例的发病机制，它是可能的，这样的缺陷可能会在临床样本中检测到，特别是脑脊液（CSF）。该试验项目旨在直接确定CSF中Ab降解的改变是否可能构成AD的可靠生物标志物。来自少量样本的初步结果表明，相对于年龄匹配的对照组，AD患者CSF中的Ab catalase显著降低。该试验资助旨在比较AD病例和对照组大量CSF样本中Ab降解（目标1）的相对速率和A2水解（目标2）的特定位点。此外，我们将开始通过抑制剂谱确定CSF中存在的A2降解蛋白酶的特性（目的3）。这些初步研究将确定使用CSF A2催化剂作为AD生物标志物的优点。如果成功的话，这项试验性研究的结果可作为今后供资建议的基础。 公共卫生相关性：该提案将探讨通过脑脊液（CSF）中的酶活性检测和监测阿尔茨海默病（AD）的可能方法。具体来说，我们将研究从AD患者和正常人获得的CSF样本内的淀粉样蛋白2-蛋白（A2）的清除的不同方面。该项目可以提高我们检测AD的能力，可能在临床症状出现之前，这将大大有助于治疗或预防这种使人衰弱的疾病。

DESCRIPTION (provided by applicant): Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by abnormal accumulation of the amyloid b-protein (Ab) in brain regions subserving memory and cognition. Emerging evidence suggests that defects in the proteolytic degradation of Ab may contribute to the pathogenesis of a substantial fraction of idiopathic AD cases, and it is possible that such defects might be detected in clinical samples, particularly the cerebrospinal fluid (CSF). This pilot project seeks to directly determine whether alterations in Ab degradation in CSF might constitute a reliable biomarker for AD. Preliminary results from a small number of samples suggests that Ab catabolism within the CSF of AD patients is significantly reduced relative to age-matched controls. This pilot grant seeks to compare the relative rates of Ab degradation (Aim 1) and the specific site(s) of A2 hydrolysis (Aim 2) in a larger number of CSF samples from AD cases and controls. Furthermore, we will begin to establish the identity of the A2-degrading protease(s) present in CSF through inhibitor profiling (Aim 3). These pilot studies will establish the merit of using CSF A2 catabolism as a biomarker for AD. If successful, the results obtained from this pilot study could be used as the basis for future funding proposals. PUBLIC HEALTH RELEVANCE: This proposal will investigate a possible method for detecting and monitoring Alzheimer disease (AD), through enzyme activities in the cerebrospinal fluid (CSF), the liquid surrounding the brain. Specifically, we will examine different aspects of the clearance of the amyloid 2-protein (A2) within CSF samples obtained from AD patients and normal individuals. This project could improve our ability to detect AD, possibly prior to the onset of clinical symptoms, which will greatly facilitate the treatment or prevention of this debilitating disease.