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

描述(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，其特征是淀粉样b蛋白(Ab)在大脑中为记忆和认知服务的区域异常堆积。新的证据表明，抗体的蛋白降解缺陷可能与相当一部分特发性AD病例的发病有关，而且这种缺陷可能在临床标本中检测到，特别是脑脊液(CSF)。这个试点项目试图直接确定脑脊液中抗体降解的变化是否可能构成AD的可靠生物标志物。来自少量样本的初步结果表明，与年龄匹配的对照组相比，AD患者脑脊液中的抗体分解代谢显著减少。这项试点拨款旨在比较AD患者和对照的大量脑脊液样本中抗体降解的相对速度(目标1)和A2水解的特定位置(S)(目标2)。此外，我们将开始通过抑制物图谱(目标3)来确定存在于脑脊液中的A2降解蛋白水解酶(S)的身份。这些先导性研究将确立使用脑脊液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作为今后资金提议的基础。

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.