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

Amyloid-beta peptide (A beta) plaque in the brain is the primary (post mortem) diagnostic criterion of Alzheimer's disease (AD). The physiological role(s) of A beta are poorly understood. We have previously determined an A beta interacting domain (A beta ID) 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 A beta ID interacts in a DNA sequence-specific manner with A beta. We now demonstrate novel A beta activity as a possible transcription factor. Herein, we detected A beta-chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma (SK-N-SH) cells treated with FITC conjugated A beta 1-40 localized A beta 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 A beta peptides and/or H2O2. A beta treatment of cell cultures produced a DNA sequence-specific response in cells transfected with polymorphic APP clones. Our results suggest the A beta peptide may regulate its own production through feedback on its precursor protein and BACE1, leading to amyloidogenesis in AD. (C) 2011 Elsevier B.V. All rights reserved.