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Journal of Biomedicine and Biotechnology
Volume 2006 (2006), Article ID 15792, 6 pages
Review Article

The TGF-β1/Upstream Stimulatory Factor-Regulated PAI-1 Gene: Potential Involvement and a Therapeutic Target in Alzheimer's Disease

Center for Cell Biology and Cancer Research, Center for Health Sciences, Albany, NY 12208, USA

Received 29 November 2005; Revised 23 February 2006; Accepted 28 February 2006

Copyright © 2006 Paul J. Higgins. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Amyloid peptide (Aβ) aggregates, derived from initial β-site proteolytic processing of the amyloid precursor protein (APP), accumulate in the brains of Alzheimer's disease patients. The plasmin-generating cascade appears to serve a protective role in the central nervous system since plasmin-mediated proteolysis of APP utilizes the α site, eventually generating nontoxic peptides, and plasmin also degrades Aβ. The conversion of plasminogen to plasmin by tissue-type plasminogen activator in the brain is negatively regulated by plasminogen activator inhibitor type-1 (PAI-1) resulting in attenuation of plasmin-dependent substrate degradation with resultant accumulation of Aβ. PAI-1 and its major physiological inducer TGF-β1, moreover, are increased in models of Alzheimer's disease and have been implicated in the etiology and progression of human neurodegenerative disorders. This review highlights the potential role of PAI-1 and TGF-β1 in this process. Current molecular events associated with TGF-β1-induced PAI-1 transcription are presented with particular relevance to potential targeting of PAI-1 gene expression as a molecular approach to the therapy of neurodegenerative diseases associated with increased PAI-1 expression such as Alzheimer's disease.