Ageing and amyloid-beta peptide deposition contribute to an impaired brain tissue plasminogen activator activity by different mechanisms

作者：Cacquevel Mathias; Launay Severine; Castel Herve; Benchenane Karim; Cheenne Simon; Buee Luc; Moons Lieve; Delacourte Andre; Carmeliet Peter; Vivien Denis^*

来源：Neurobiology of Disease, 2007, 27(2): 164-173.

DOI：10.1016/j.nbd.2007.04.004

• tissue plasminogen activator
• ageing
• amyloid-beta peptides
• transgenic mice
• Alzheimer's disease
• PAI-1

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 (A beta). 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 A beta 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 A beta accumulation. We observed that cerebral tPA activity was decreased during ageing in normal mice and that this effect was worsened in mice overproducing A beta 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 AP 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.

• 出版日期2007-8
• 单位河北医科大学