Early Growth Response 1 (Egr-1) Is a Transcriptional Activator of β-Secretase 1 (BACE-1) in the Brain

Accumulation of amyloid- peptide (A) in the brain is regarded as central to Alzheimer's disease (AD) pathogenesis. A is generated by a sequential cleavage of amyloid precursor protein (APP) by -secretase 1 (BACE-1) followed by -secretase. BACE-1 cleavage of APP is the committed step in A synthesis. Understanding the mechanism by which BACE-1 is activated leading to A synthesis in the brain can provide better understanding of AD pathology and help to develop novel therapies. In this study, we found that the levels of A and BACE-1 are significantly reduced in the brains of mice lacking transcription factor early growth response 1 (Egr-1) when compared with the WT. We demonstrate that in COS-7 cells, Egr-1 binds to the BACE-1 promoter and activates BACE-1 transcription. In rat hippocampal primary neurons, overexpression of Egr-1 induces BACE-1 expression, activates BACE-1, promotes amyloidogenic APP processing, and enhances A synthesis. In mouse hippocampal primary neurons, knockdown of BACE-1 almost completely blocks Egr-1-induced amyloidogenic APP processing and A synthesis. Our data indicate that Egr-1 promotes A synthesis via transcriptional activation of BACE-1 and suggest that Egr-1 plays role in activation of BACE-1 and acceleration of A synthesis in AD brain. Egr-1 is a potential therapeutic target for AD.