title: The TGF-beta1/upstream stimulatory factor-regulated PAI-1 gene: potential involvement and a therapeutic target in Alzheimer's disease.
abstract: Amyloid peptide (A beta) aggregates, derived from initial beta-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 alpha site, eventually generating nontoxic peptides, and plasmin also degrades A beta. 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 A beta. PAI-1 and its major physiological inducer TGF-beta1, 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-beta1 in this process. Current molecular events associated with TGF-beta1-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.
authors.affiliation: Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Higgins