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Enhanced clearance of Abeta in brain by sustaining the plasmin proteolysis cascade.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2008 Jun 24; Vol. 105 (25), pp. 8754-9. Date of Electronic Publication: 2008 Jun 16. - Publication Year :
- 2008
-
Abstract
- The amyloid hypothesis states that a variety of neurotoxic beta-amyloid (Abeta) species contribute to the pathogenesis of Alzheimer's disease. Accordingly, a key determinant of disease onset and progression is the appropriate balance between Abeta production and clearance. Enzymes responsible for the degradation of Abeta are not well understood, and, thus far, it has not been possible to enhance Abeta catabolism by pharmacological manipulation. We provide evidence that Abeta catabolism is increased after inhibition of plasminogen activator inhibitor-1 (PAI-1) and may constitute a viable therapeutic approach for lowering brain Abeta levels. PAI-1 inhibits the activity of tissue plasminogen activator (tPA), an enzyme that cleaves plasminogen to generate plasmin, a protease that degrades Abeta oligomers and monomers. Because tPA, plasminogen and PAI-1 are expressed in the brain, we tested the hypothesis that inhibitors of PAI-1 will enhance the proteolytic clearance of brain Abeta. Our data demonstrate that PAI-1 inhibitors augment the activity of tPA and plasmin in hippocampus, significantly lower plasma and brain Abeta levels, restore long-term potentiation deficits in hippocampal slices from transgenic Abeta-producing mice, and reverse cognitive deficits in these mice.
- Subjects :
- Animals
Humans
Immunohistochemistry
Mice
Mice, Transgenic
Plasminogen Inactivators metabolism
Tissue Plasminogen Activator antagonists & inhibitors
Tissue Plasminogen Activator metabolism
Amyloid beta-Peptides metabolism
Brain metabolism
Fibrinolysin metabolism
Fibrinolytic Agents metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 105
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 18559859
- Full Text :
- https://doi.org/10.1073/pnas.0710823105