Oxidative stress potentiates BACE1 gene expression and Abeta generation

Alzheimer's Disease (AD) is the most common neurodegenerative disorder leading to dementia and its prevalence increases with age. The pathological features of AD are characterized by the beta-amyloid protein (A(beta)) deposits in the core of neuritic plaques and abnormal neurofibrillary tangles in the brain of AD patients. BACE1 is the major beta-secretase to cleave the beta-amyloid precursor protein (APP) to generate A(beta). Oxidative stress has been shown to affect A(beta) generation in the AD pathogenesis and the mechanism of such effect is unknown. In this report we generated a novel promoterless enhanced green fluorescent protein (EGFP) reporter gene cloning vector and cloned a 1.9-kb BACE1 gene promoter fragment in this vector. The BACE1 promoter fragment can efficiently activate EGFP or luciferase gene transcription. Oxidative stress induced by hydrogen peroxide resulted in significant increase in the BACE1 promoter activity. Furthermore, hydrogen peroxide treatment facilitated beta-secretase activity and A(beta) generation. Thus, upregulation of BACE1 transcription by oxidative stress may contribute to the pathogenesis of Alzheimer's disease.