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• W2512634905 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. 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." @default.
• W2512634905 created "2016-09-16" @default.
• W2512634905 creator A5005438582 @default.
• W2512634905 creator A5037694066 @default.
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• W2512634905 date "2016-10-01" @default.
• W2512634905 modified "2023-10-16" @default.
• W2512634905 title "Early Growth Response 1 (Egr-1) Is a Transcriptional Activator of β-Secretase 1 (BACE-1) in the Brain" @default.
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• W2512634905 doi "https://doi.org/10.1074/jbc.m116.738849" @default.
• W2512634905 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5064006" @default.
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• W2512634905 hasPublicationYear "2016" @default.
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