title: The Alzheimer's amyloid β-peptide (Aβ) binds a specific DNA Aβ-interacting domain (AβID) in the APP, BACE1, and APOE promoters in a sequence-specific manner: characterizing a new regulatory motif.
abstract: Deposition of extracellular plaques, primarily consisting of amyloid β peptide (Aβ), in the brain is the confirmatory diagnostic of Alzheimer's disease (AD); however, the physiological and pathological role of Aβ is not fully understood. Herein, we demonstrate novel Aβ activity as a putative transcription factor upon AD-associated genes. We used oligomers from 5'-flanking regions of the apolipoprotein E (APOE), Aβ-precursor protein (APP) and β-amyloid site cleaving enzyme-1 (BACE1) genes for electrophoretic mobility shift assay (EMSA) with different fragments of the Aβ peptide. Our results suggest that Aβ bound to an Aβ-interacting domain (AβID) with a consensus of "KGGRKTGGGG". This peptide-DNA interaction was sequence specific, and mutation of the first "G" of the decamer's terminal "GGGG" eliminated peptide-DNA interaction. Furthermore, the cytotoxic Aβ25-35 fragment had greatest DNA affinity. Such specificity of binding suggests that the AβID is worth of further investigation as a site wherein the Aβ peptide may act as a transcription factor.
authors.affiliation: Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Maloney
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D001483:Base Sequence; D016384:Consensus Sequence; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D010446:Peptide Fragments / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D010446:Peptide Fragments; D014157:Transcription Factors; C074636:amyloid beta-protein (25-35); D004247:DNA; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human