title: Functional activity of the novel Alzheimer's amyloid β-peptide interacting domain (AβID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesis.
abstract: Amyloid-β peptide (Aβ) plaque in the brain is the primary (post mortem) diagnostic criterion of Alzheimer's disease (AD). The physiological role(s) of Aβ are poorly understood. We have previously determined an Aβ interacting domain (AβID) in the promoters of AD-associated genes (Maloney and Lahiri, 2011. Gene. 15,doi:10.1016/j.gene.2011.06.004. epub ahead of print.). This AβID interacts in a DNA sequence-specific manner with Aβ. We now demonstrate novel Aβ activity as a possible transcription factor. Herein, we detected Aβ-chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma (SK-N-SH) cells treated with FITC conjugated Aβ1-40 localized Aβ to the nucleus in the presence of H2O2-mediated oxidative stress. Furthermore, primary rat fetal cerebrocortical cultures were transfected with APP and BACE1 promoter-luciferase fusions, and rat PC12 cultures were transfected with polymorphic APP promoter-CAT fusion clones. Transfected cells were treated with different Aβ peptides and/or H2O2. Aβ treatment of cell cultures produced a DNA sequence-specific response in cells transfected with polymorphic APP clones. Our results suggest the Aβ peptide may regulate its own production through feedback on its precursor protein and BACE1, leading to amyloidogenesis in AD.
authors.affiliation: Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Bailey
authors.forename: Bryan
authors.initials: B
authors.lastname: Maloney
authors.forename: Yuan-Wen
authors.initials: YW
authors.lastname: Ge
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D000682:Amyloid / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D016716:PC12 Cells; D017434:Protein Structure, Tertiary; D051381:Rats
chemical_list: C545487:APP protein, human; D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human