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

Neurobiology of Disease

Karim Benchenane¹  Simon Chéenne¹  Mathias Cacquevel¹  Séverine Launay¹  Hervé Castel¹  Denis Vivien¹  Luc Buée²  André Delacourte²  Peter Carmeliet³  Lieve Moons³ 

[1] INSERM, INSERM-Avenir, «tPA in the working brain», Caen, France, Université de Caen-Basse-Normandie, Caen, France, GIP CYCERON, Boulevard Henri Becquerel, BP5229, Caen, F-14074, France;INSERM, U815, Institut de Médecine Prédictive et de Recherche Thérapeutique, Place de Verdun, Lille, F-59045, France;The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology (VIB), KU Leuven, Campus Gasthuisberg, Leuven, B-3000, Belgium;

关键词: Tissue plasminogen activator;    Ageing;    Amyloid-beta peptides;    Transgenic mice;    Alzheimer’s disease;    PAI-1;   

DOI  :  

来源: DOAJ

【 摘 要 】

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

【 授权许可】

Unknown