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

Accumulation of amyloid-ß peptide (Aß) in the brain is regarded as central to Alzheimer's disease (AD) pathogenesis. Aß is generated by a sequential cleavage of amyloid precursor protein (APP) by ß-secretase 1 (BACE-1) followed by γ-secretase. BACE-1 cleavage of APP is the committed step in Aß synthesis. Understanding the mechanism by which BACE-1 is activated leading to Aß 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 Aß 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 Aß synthesis. In mouse hippocampal primary neurons, knockdown of BACE-1 almost completely blocks Egr-1-induced amyloidogenic APP processing and Aß synthesis. Our data indicate that Egr-1 promotes Aß synthesis via transcriptional activation of BACE-1 and suggest that Egr-1 plays role in activation of BACE-1 and acceleration of Aß synthesis in AD brain. Egr-1 is a potential therapeutic target for AD.