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[摘要]：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 H(2)O(2)-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 H(2)O(2). 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. |
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