Ageing and amyloid-beta peptide deposition contribute to an impaired brain tissue plasminogen activator activity by different mechanisms.
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.
Cacquevel
Mathias
M
INSERM, INSERM-Avenir, tPA in the working brain, Caen, France.
Launay
Séverine
S
Castel
Hervé
H
Benchenane
Karim
K
Chéenne
Simon
S
Buée
Luc
L
Moons
Lieve
L
Delacourte
André
A
Carmeliet
Peter
P
Vivien
Denis
D
D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000201:enzymology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; D010959:Tissue Plasminogen Activator