Taking Down the Unindicted Co-Conspirators of Amyloid β-Peptidemediated Neuronal Death: Shared Gene Regulation of BACE1 and APP Genes Interacting with CREB, Fe65 and YY1 Transcription Factors

Author(s): Debomoy K. Lahiri , Yuan-Wen Ge , Jack T. Rogers , Kumar Sambamurti , Nigel H. Greig , Bryan Maloney .

Journal Name: Current Alzheimer Research

Volume 3 , Issue 5 , 2006

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Abstract:

Major hallmarks of Alzheimers disease (AD) include brain deposition of the amyloid-β peptide (Aβ), which is proteolytically cleaved from a large Aβ precursor protein (APP) by β and β- secretases. A transmembrane aspartyl protease, β-APP cleaving enzyme (BACE1), has been recognized as the β-secretase. We review the structure and function of the BACE1 protein, and of 4129 bp of the 5-flanking region sequence of the BACE1 gene and its interaction with various transcription factors involved in cell signaling. The promoter region and 5-untranslated region (UTR) contain multiple transcription factor binding sites, such as AP-1, CREB and MEF2. A 91 bp fragment is the shortest region with significant reporter gene activity and constitutes the minimal promoter element for BACE1. The BACE1 promoter contains six unique functional domains and three structural domains of increasing sequence complexity as the “ATG” start codon is approached. Notably, the BACE1 gene promoter contains basal regulatory elements, inducible features and sites for regulation by various important transcription factors. Herein, we also discuss and speculate how the interaction of these transcription factors with the BACE1 promoter can modulate synaptic plasticity, neuronal apoptosis and oxidative stress, which are pertinent to the pathogenesis and progression of AD.

Keywords: mRNA EXPRESSION, inflammation, BACE1 homologue, cAMP response element-binding (CREB) sites, chloramphenicol acetyltransferase (CAT) reporter

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Article Details

VOLUME: 3
ISSUE: 5
Year: 2006
Page: [475 - 483]
Pages: 9
DOI: 10.2174/156720506779025224
Price: $58

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