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

Paul J Higgins

doi:10.1155/jbb/2006/15792

Abstract

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.

Highlights

In patients with Alzheimer’s disease (AD), plaques comprised of aggregated β-amyloid peptides (Aβ) accumulate in specific areas of the brain as a consequence of the proteolytic processing of the single-pass transmembrane amyloid precursor protein (APP) [1]
Aβ peptides are derived from APP by βsite cleavage by an aspartic protease (BACE) producing a membrane-bound COOH-terminal C99 fragment followed by a complex proteolytic event at the C99 transmembrane-localized γ position [3,4,5]
Plasmin levels in the brains of AD patients are considerably reduced [10] further supporting a causal relationship between deficient activity of the plasmin-generating proteolytic system and accumulation of Aβ in the progression of AD

Summary

Review Article

The TGF-β1/Upstream Stimulatory Factor-Regulated PAI-1 Gene: Potential Involvement and a Therapeutic Target in Alzheimer’s Disease. 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. PAI-1 and its major physiological inducer TGF-β1, 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-β1induced 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

INTRODUCTION

Target substrates

DNase protected

Neutralizing Ab