title: Inhibition of Abeta production by NF-kappaB inhibitors.
abstract: The transcription factor nuclear factor kappaB (NF-kappaB) is widely expressed in the nervous system and increased NF-kappaB immunoreactivity has been observed in Alzheimer's disease (AD) brains in the nuclei of neurons within the vicinity of diffuse beta-amyloid plaques. Beta-amyloid (Abeta) peptides are the main constituent of senile plaques and are known to stimulate NF-kappaB activity. In the present study, we investigated the effect of various NF-kappaB inhibitors on the production of Abeta1-40, Abeta1-42, secreted APP (sAPPbeta and sAPPalpha) and APP C-terminal fragments (APP-CTF) using CHO cells overexpressing the beta-amyloid precursor protein (APP). Our data show that NF-kappaB inhibitors decrease both Abeta1-40 and Abeta1-42 production. In addition, we show that some NF-kappaB inhibitors decrease sAPPbeta and APP-CTFbeta suggesting that they reduce the beta-secretase cleavage of APP. Altogether our data suggest that NF-kappaB inhibitors may be of therapeutic importance for the treatment of AD pathology not only by blocking inflammatory processes but also by directly inhibiting the production of Abeta peptides.
authors.affiliation: Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA. dparis@rfdn.org
authors.forename: Daniel
authors.initials: D
authors.lastname: Paris
authors.forename: Nikunj
authors.initials: N
authors.lastname: Patel
authors.forename: Amita
authors.initials: A
authors.lastname: Quadros
authors.forename: Monica
authors.initials: M
authors.lastname: Linan
authors.forename: Pancham
authors.initials: P
authors.lastname: Bakshi
authors.forename: Ghania
authors.initials: G
authors.lastname: Ait-Ghezala
authors.forename: Michael
authors.initials: M
authors.lastname: Mullan
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism; D010455:Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D058225:Plaque, Amyloid / Q000187:drug effects* / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010455:Peptides; D011500:Protein Synthesis Inhibitors; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases