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，其特征是b-淀粉样蛋白（Ab）在大脑负责记忆和认知的区域异常积累。新出现的证据表明，Ab蛋白水解降解中的缺陷可能导致了相当一部分特发性AD病例的发病机制，并且有可能在临床样本，特别是脑脊液（CSF）中检测到这种缺陷。该试点项目旨在直接确定脑脊液中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患者脑脊液中的Ab分解代谢显著降低。该试点资助旨在比较来自AD病例和对照组的大量CSF样本中Ab降解（Aim 1）的相对速率和A2水解（Aim 2）的特定位点。此外，我们将通过抑制剂分析开始确定脑脊液中存在的a2降解蛋白酶的身份（Aim 3）。这些初步研究将确定使用CSF A2分解代谢作为AD生物标志物的优点。如果成功，从这项试点研究中获得的结果可以用作今后供资建议的基础。

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.