Advances in Alzheimer's Research

Volume: 1

Indexed in: EBSCO, Ulrich's Periodicals Directory

Alzheimer’s disease (AD) is currently recognized as an untreatable, progressive, degenerative and terminal disease that is globally afflicting an estimated 36 million people and this number is ...
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Taking Down the Unindicted Co-Conspirators of Amyloid β-Peptide-Mediated Neuronal Death: Shared Gene Regulation of BACE1 and APP Genes Interacting with CREB, Fe65 and YY1 Transcription Factors

Pp. 128-146 (19)

Debomoy K. Lahiri, Yuan-Wen Ge, Jack T. Rogers, Kumar Sambamurti, Nigel H. Greig and Bryan Maloney

Abstract

Major hallmarks of Alzheimer’s 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 γ– 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:

Amyloid, Aβ precursor protein (APP), β–secretases, γ–secretases, BACE1, Down syndrome, transcription factors, Fe65 protein gene.

Affiliation:

Indiana University School of Medicine, Department of Psychiatry, Institute of Psychiatric Research, 791 Union Drive, Indianapolis, IN 46202, USA.