Searcy James L, Le Bihan Thierry, Salvadores Natalia, McCulloch James, Horsburgh Karen
Centre for Neuroregeneration, University of Edinburgh, Edinburgh, United Kingdom.
SynthSys - Synthetic & Systems Biology, University of Edinburgh, Edinburgh, United Kingdom ; Institute of Structural and Molecular Biology, University of Edinburgh, Edinburgh, United Kingdom.
PLoS One. 2014 Feb 26;9(2):e89970. doi: 10.1371/journal.pone.0089970. eCollection 2014.
The structural integrity of cerebral vessels is compromised during ageing. Abnormal amyloid (Aβ) deposition in the vasculature can accelerate age-related pathologies. The cerebrovascular response associated with ageing and microvascular Aβ deposition was defined using quantitative label-free shotgun proteomic analysis. Over 650 proteins were quantified in vessel-enriched fractions from the brains of 3 and 9 month-old wild-type (WT) and Tg-SwDI mice. Sixty-five proteins were significantly increased in older WT animals and included several basement membrane proteins (nidogen-1, basement membrane-specific heparan sulfate proteoglycan core protein, laminin subunit gamma-1 precursor and collagen alpha-2(IV) chain preproprotein). Twenty-four proteins were increased and twenty-one decreased in older Tg-SwDI mice. Of these, increases in Apolipoprotein E (APOE) and high temperature requirement serine protease-1 (HTRA1) and decreases in spliceosome and RNA-binding proteins were the most prominent. Only six shared proteins were altered in both 9-month old WT and Tg-SwDI animals. The age-related proteomic response in the cerebrovasculature was distinctly different in the presence of microvascular Aβ deposition. Proteins found differentially expressed within the WT and Tg-SwDI animals give greater insight to the mechanisms behind age-related cerebrovascular dysfunction and pathologies and may provide novel therapeutic targets.
在衰老过程中，脑血管的结构完整性会受到损害。血管中异常的淀粉样蛋白（Aβ）沉积会加速与年龄相关的病变。通过定量无标记鸟枪法蛋白质组学分析确定了与衰老和微血管Aβ沉积相关的脑血管反应。在3个月和9个月大的野生型（WT）和Tg-SwDI小鼠大脑的血管富集部分中，对650多种蛋白质进行了定量分析。在老年WT动物中，65种蛋白质显著增加，包括几种基底膜蛋白（巢蛋白-1、基底膜特异性硫酸乙酰肝素蛋白聚糖核心蛋白、层粘连蛋白γ-1亚基前体和胶原蛋白α-2(IV)链前体蛋白）。在老年Tg-SwDI小鼠中，24种蛋白质增加，21种蛋白质减少。其中，载脂蛋白E（APOE）和高温需求丝氨酸蛋白酶-1（HTRA1）的增加以及剪接体和RNA结合蛋白的减少最为显著。在9个月大的WT和Tg-SwDI动物中，只有6种共同的蛋白质发生了改变。在存在微血管Aβ沉积的情况下，脑血管中与年龄相关的蛋白质组反应明显不同。在WT和Tg-SwDI动物中发现差异表达的蛋白质，能更深入地了解与年龄相关的脑血管功能障碍和病变背后的机制，并可能提供新的治疗靶点。
