Manousopoulou Antigoni, Yuen Ho Ming, Sharp Matthew MacGregor, Saito Satoshi, Aldea Roxana, Mazer Norman, Garbis Spiros D, Carare Roxana O
Beckman Research Institute, City of Hope, Duarte, CA, USA.
Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
Free Neuropathol. 2020 Oct 8;1:28. doi: 10.17879/freeneuropathology-2020-2955. eCollection 2020 Jan.
Cerebral amyloid angiopathy (CAA) is the accumulation of amyloid beta (Aβ) in the walls of cerebral arterioles, arteries and capillaries. Changes in the white matter in CAA are observed as hyperintensities and dilated perivascular spaces on MRI suggesting impairment of fluid drainage but the pathophysiology behind these changes is poorly understood. We tested the hypothesis that proteins associated with clearance of Aβ peptides are upregulated in the white matter in cases of CAA. In this study, we compare the quantitative proteomic profile of white matter from post-mortem brains of patients with CAA and age-matched controls in order to gain insight into the cellular processes and key molecules involved in the pathophysiology of CAA. Our proteomic analysis resulted in the profiling of 3,734 proteins (peptide FDR p<0.05). Of these, 189 were differentially expressed in CAA vs. control. Bioinformatics analysis of these proteins showed significant enrichment of proteins related to cell adhesion | cell-matrix interaction, mitochondrial dysfunction and hypoxia. Upregulated proteins in CAA included EMILIN2, COL4A2, TLN1, CLU, HSPG2. Downregulated proteins included DSP, IDE, HBG1. The present study reports an in-depth quantitative proteomic profiling of white matter from patients with CAA, highlighting extracellular matrix proteins and clusterin as key molecules in the pathophysiology of white matter changes in cases of CAA.
脑淀粉样血管病（CAA）是指淀粉样β蛋白（Aβ）在脑小动脉、动脉和毛细血管壁内积聚。CAA患者白质的变化在磁共振成像（MRI）上表现为高信号和扩张的血管周围间隙，提示液体引流受损，但这些变化背后的病理生理学机制尚不清楚。我们检验了以下假设：在CAA病例中，与Aβ肽清除相关的蛋白质在白质中上调。在本研究中，我们比较了CAA患者和年龄匹配对照者死后大脑白质的定量蛋白质组学谱，以深入了解CAA病理生理学中涉及的细胞过程和关键分子。我们的蛋白质组学分析鉴定出了3734种蛋白质（肽段错误发现率p<0.05）。其中，189种在CAA组与对照组中差异表达。对这些蛋白质的生物信息学分析显示，与细胞黏附、细胞-基质相互作用、线粒体功能障碍和缺氧相关的蛋白质显著富集。CAA中上调的蛋白质包括埃米林2（EMILIN2）、IV型胶原α2链（COL4A2）、张力蛋白1（TLN1）、簇集素（CLU）、硫酸乙酰肝素蛋白聚糖2（HSPG2）。下调的蛋白质包括桥粒斑蛋白（DSP）、胰岛素降解酶（IDE）、血红蛋白γ-1（HBG1）。本研究报告了CAA患者白质的深度定量蛋白质组学谱，突出了细胞外基质蛋白和簇集素是CAA病例中白质变化病理生理学的关键分子。
