The TGF-β1/upstream stimulatory factor-regulated PAI-1 gene:: Potential involvement and a therapeutic target in Alzheimer's disease

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 a 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-beta 1, 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-beta 1 in this process. Current molecular events associated with TGF-beta 1-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.