Cacquevel Mathias, Launay Séverine, Castel Hervé, Benchenane Karim, Chéenne Simon, Buée Luc, Moons Lieve, Delacourte André, Carmeliet Peter, Vivien Denis
INSERM, INSERM-Avenir, tPA in the working brain, Caen, France.
Neurobiol Dis. 2007 Aug;27(2):164-73. doi: 10.1016/j.nbd.2007.04.004. Epub 2007 Apr 24.
Alzheimer's disease (AD) is the most common form of neurodegenerative disorder in the ageing population. It is characterized by the cerebral accumulation of toxic amyloid-beta peptide assemblies (Abeta). The serine protease plasmin, which is generated from the inactive zymogen plasminogen through its proteolytic cleavage by tissue- (tPA) or urokinase-type plasminogen activator, has been implicated in the catabolism of Abeta peptides. In this report, we studied the regulation of tPA activity in vivo during ageing in normal mice and in a mouse model of AD characterized by an exacerbated endogenous Abeta accumulation. We observed that cerebral tPA activity was decreased during ageing in normal mice and that this effect was worsened in mice overproducing Abeta peptides. These phenomena result, respectively, from a decrease in tPA expression and from an increase in the production of one of the tPA inhibitors, the plasminogen activator inhibitor type 1 (PAI-1). A similar study in sporadic AD and age-matched control brain tissues revealed that the tPA proteolytic activity was negatively correlated to Abeta peptides levels supporting the data observed in mice. Altogether, our data support a model in which amyloid deposition induces a decrease in tPA activity through the overproduction of PAI-1 by activated glial cells.
阿尔茨海默病（AD）是老年人群中最常见的神经退行性疾病形式。其特征是有毒的淀粉样β肽聚集体（Aβ）在大脑中积累。丝氨酸蛋白酶纤溶酶由无活性的酶原纤溶酶原通过组织型纤溶酶原激活物（tPA）或尿激酶型纤溶酶原激活物的蛋白水解切割产生，它与Aβ肽的分解代谢有关。在本报告中，我们研究了正常小鼠衰老过程中以及以内源性Aβ积累加剧为特征的AD小鼠模型中体内tPA活性的调节。我们观察到正常小鼠衰老过程中脑内tPA活性降低，并且在过量产生Aβ肽的小鼠中这种效应更严重。这些现象分别是由于tPA表达降低以及tPA抑制剂之一纤溶酶原激活物抑制剂1型（PAI - 1）产生增加所致。对散发性AD和年龄匹配的对照脑组织进行的类似研究表明，tPA蛋白水解活性与Aβ肽水平呈负相关，这支持了在小鼠中观察到的数据。总之，我们的数据支持一种模型，即淀粉样蛋白沉积通过激活的神经胶质细胞过量产生PAI - 1诱导tPA活性降低。
