Differential regulation of BACE1 promoter activity by nuclear factor-kappaB in neurons and glia upon exposure to beta-amyloid peptides.
The brains of Alzheimer's disease (AD) patients display cerebrovascular and parenchymal deposits of beta-amyloid (A beta) peptides, which are derived by proteolytic processing by the beta-site APP-cleaving enzyme 1 (BACE1) of the amyloid precursor protein (APP). The rat BACE1 promoter has a nuclear factor-kappaB (NF-kappaB) binding site. Deletion studies with a BACE1 promoter/luciferase reporter suggest that the NF-kappaB binding DNA consensus sequence plays a suppressor role, when occupied by NF-kappaB, in the regulation of neuronal brain BACE1 expression. Here we characterize a signal transduction pathway that may be responsible for the increases in A beta associated with AD. We propose that the transcription factor NF-kappaB acts as a repressor in neurons but as an activator of BACE1 transcription in activated astrocytes present in the CNS under chronic stress, a feature present in the AD brain. The activated astrocytic stimulation of BACE1 may in part account for increased BACE1 transcription and subsequent processing of Ab eta in a cell-specific manner in the aged and AD brain. As measured by reporter gene promoter constructs and endogenous BACE1 protein expression, a functional NF-kappaB site was stimulatory in activated astrocytes and A beta-exposed neuronal cells and repressive in neuronal and nonactivated astrocytic cells. Given the evidence for increased levels of activated astrocytes in the aged brain, the age- and AD-associated increases in NF-kappaB in brain may be significant contributors to increases in A beta, acting as a positive feedback loop of chronic inflammation, astrocyte activation, increased p65/p50 activation of BACE1 transcription, and further inflammation.
Bourne
Krystyn Z
KZ
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555-1072, USA.
Ferrari
Diana C
DC
Lange-Dohna
Christine
C
Rossner
Steffen
S
Wood
Thomas G
TG
Perez-Polo
J Regino
JR
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005260:Female; D005480:Flurbiprofen / Q000494:pharmacology; D006168:Guinea Pigs; D006624:Hippocampus; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009154:Mutation / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000502:physiology*; D051381:Rats; D014162:Transfection / Q000379:methods
D016229:Amyloid beta-Peptides; D016861:Cyclooxygenase Inhibitors; D016328:NF-kappa B; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D005480:Flurbiprofen; D020932:Nerve Growth Factor; D006861:Hydrogen Peroxide; D053829:Amyloid Precursor Protein Secretases