, Volume 112, Issue 3, pp 455-469

Oxidative stress potentiates BACE1 gene expression and Aβ generation

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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 β-amyloid protein (Aβ) deposits in the core of neuritic plaques and abnormal neurofibrillary tangles in the brain of AD patients. BACE1 is the major β-secretase to cleave the β-amyloid precursor protein (APP) to generate Aβ. Oxidative stress has been shown to affect Aβ 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 β-secretase activity and Aβ generation. Thus, upregulation of BACE1 transcription by oxidative stress may contribute to the pathogenesis of Alzheimer’s disease.