Tissue-Plasminogen Activator Attenuates Alzheimer's Disease-Related Pathology Development in APPswe/PS1 Mice.
Alzheimer's disease (AD) is the leading cause of dementia among elderly population. AD is characterized by the accumulation of beta-amyloid (Aβ) peptides, which aggregate over time to form amyloid plaques in the brain. Reducing soluble Aβ levels and consequently amyloid plaques constitute an attractive therapeutic avenue to, at least, stabilize AD pathogenesis. The brain possesses several mechanisms involved in controlling cerebral Aβ levels, among which are the tissue-plasminogen activator (t-PA)/plasmin system and microglia. However, these mechanisms are impaired and ineffective in AD. Here we show that the systemic chronic administration of recombinant t-PA (Activase rt-PA) attenuates AD-related pathology in APPswe/PS1 transgenic mice by reducing cerebral Aβ levels and improving the cognitive function of treated mice. Interestingly, these effects do not appear to be mediated by rt-PA-induced plasmin and matrix metalloproteinases 2/9 activation. We observed that rt-PA essentially mediated a slight transient increase in the frequency of patrolling monocytes in the circulation and stimulated microglia in the brain to adopt a neuroprotective phenotype, both of which contribute to Aβ elimination. Our study unraveled a new role of rt-PA in maintaining the phagocytic capacity of microglia without exacerbating the inflammatory response and therefore might constitute an interesting approach to stimulate the key populations of cells involved in Aβ clearance from the brain.
Neuroscience Laboratory, CHU de Québec Research Center (CHUL), Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec City, QC, Canada.
Ayman
A
ElAli
Neuroscience Laboratory, CHU de Québec Research Center (CHUL), Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec City, QC, Canada.
Maude
M
Bordeleau
Neuroscience Laboratory, CHU de Québec Research Center (CHUL), Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec City, QC, Canada.
Peter
P
Thériault
Neuroscience Laboratory, CHU de Québec Research Center (CHUL), Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec City, QC, Canada.
Mohammed
M
Filali
Neuroscience Laboratory, CHU de Québec Research Center (CHUL), Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec City, QC, Canada.
Antoine
A
Lampron
Neuroscience Laboratory, CHU de Québec Research Center (CHUL), Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec City, QC, Canada.
Serge
S
Rivest
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects; D053764:Presenilin-1 / Q000235:genetics; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D010959:Tissue Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9