title: Early Growth Response 1 (Egr-1) Is a Transcriptional Activator of β-Secretase 1 (BACE-1) in the Brain.
abstract: Accumulation of amyloid-β peptide (Aβ) in the brain is regarded as central to Alzheimer's disease (AD) pathogenesis. Aβ is generated by a sequential cleavage of amyloid precursor protein (APP) by β-secretase 1 (BACE-1) followed by γ-secretase. BACE-1 cleavage of APP is the committed step in Aβ synthesis. Understanding the mechanism by which BACE-1 is activated leading to Aβ 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 Aβ 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 Aβ synthesis. In mouse hippocampal primary neurons, knockdown of BACE-1 almost completely blocks Egr-1-induced amyloidogenic APP processing and Aβ synthesis. Our data indicate that Egr-1 promotes Aβ synthesis via transcriptional activation of BACE-1 and suggest that Egr-1 plays role in activation of BACE-1 and acceleration of Aβ synthesis in AD brain. Egr-1 is a potential therapeutic target for AD.
authors: From the Lady Davis Institute for Medical Research, Jewish General Hospital, and.
authors: Xike
authors: X
authors: Qin
authors: From the Lady Davis Institute for Medical Research, Jewish General Hospital, and.
authors: Yunling
authors: Y
authors: Wang
authors: From the Lady Davis Institute for Medical Research, Jewish General Hospital, and the Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec H4H 1R3, Canada hemant.paudel@mcgill.ca.
authors: Hemant K
authors: HK
authors: Paudel
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D019556:COS Cells; D002522:Chlorocebus aethiops; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D051381:Rats; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D016229:Amyloid beta-Peptides; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C486110:Egr1 protein, rat; D015534:Trans-Activators; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; C509281:Bace1 protein, rat
keywords: amyloid-β (Aβ); early growth response protein 1 (EGR1); gene regulation; neuroscience; promoter; transcription factor