Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
NNF Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Mol Syst Biol. 2020 Jun;16(6):e9356. doi: 10.15252/msb.20199356.
Neurodegenerative diseases are a growing burden, and there is an urgent need for better biomarkers for diagnosis, prognosis, and treatment efficacy. Structural and functional brain alterations are reflected in the protein composition of cerebrospinal fluid (CSF). Alzheimer's disease (AD) patients have higher CSF levels of tau, but we lack knowledge of systems-wide changes of CSF protein levels that accompany AD. Here, we present a highly reproducible mass spectrometry (MS)-based proteomics workflow for the in-depth analysis of CSF from minimal sample amounts. From three independent studies (197 individuals), we characterize differences in proteins by AD status (> 1,000 proteins, CV < 20%). Proteins with previous links to neurodegeneration such as tau, SOD1, and PARK7 differed most strongly by AD status, providing strong positive controls for our approach. CSF proteome changes in Alzheimer's disease prove to be widespread and often correlated with tau concentrations. Our unbiased screen also reveals a consistent glycolytic signature across our cohorts and a recent study. Machine learning suggests clinical utility of this proteomic signature.
神经退行性疾病的负担日益加重，因此迫切需要更好的生物标志物来进行诊断、预后和评估治疗效果。脑脊髓液（CSF）中的蛋白质组成反映了大脑的结构和功能变化。阿尔茨海默病（AD）患者的脑脊液中 tau 蛋白水平较高，但我们对 AD 患者伴随的脑脊液蛋白水平的系统变化知之甚少。在这里，我们提出了一种高度可重复的基于质谱（MS）的蛋白质组学工作流程，用于对少量脑脊液样本进行深入分析。通过三项独立研究（197 人），我们根据 AD 状态（>1000 种蛋白质，CV<20%）描述了蛋白质的差异。与神经退行性变相关的蛋白质，如 tau、SOD1 和 PARK7，在 AD 状态下的差异最大，为我们的方法提供了强有力的阳性对照。AD 患者的脑脊液蛋白质组变化广泛，且通常与 tau 浓度相关。我们的无偏筛选还揭示了在我们的队列和最近的一项研究中存在一致的糖酵解特征。机器学习表明该蛋白质组学特征具有临床应用价值。
