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

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Abstract

Amyloid peptide (Aβ) aggregates, derived from initialβ-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-1expression such as Alzheimer's disease. Copyright © 2006 Paul J. Higgins.

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Higgins, P. J. (2006). The TGF-β1/upstream stimulatory factor-regulated PAI-1 gene: Potential involvement and a therapeutic target in Alzheimer’s disease. Journal of Biomedicine and Biotechnology. https://doi.org/10.1155/JBB/2006/15792

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