The TGF-β1/Upstream Stimulatory Factor-Regulated PAI-1 Gene:Potential Involvement and a Therapeutic Targetin Alzheimer'sDisease

[摘要] Amyloid peptide (Aβ) aggregates, derived from initialβ-site proteolytic processing of the amyloid precursorprotein (APP), accumulate in the brains of Alzheimer's diseasepatients. The plasmin-generating cascade appears to serve aprotective role in the central nervous system sinceplasmin-mediated proteolysis of APP utilizes theαsite,eventually generating nontoxic peptides, and plasmin also degradesAβ. The conversion of plasminogen to plasmin by tissue-typeplasminogen activator in the brain is negatively regulated byplasminogen activator inhibitor type-1 (PAI-1) resulting inattenuation of plasmin-dependent substrate degradation withresultant accumulation of Aβ. PAI-1 and its majorphysiological inducer TGF-β1, moreover, are increased inmodels of Alzheimer's disease and have been implicated in theetiology and progression of human neurodegenerative disorders.This review highlights the potential role of PAI-1 and TGF-β1in this process. Current molecular events associated withTGF-β1-induced PAI-1 transcription are presented withparticular relevance to potential targeting of PAI-1 geneexpression as a molecular approach to the therapy ofneurodegenerative diseases associated with increased PAI-1expression such as Alzheimer's disease.

[学科分类] 基础医学