Inhibition of Abeta production by NF-kappaB inhibitors.
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.
Paris
Daniel
D
Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA. dparis@rfdn.org
Patel
Nikunj
N
Quadros
Amita
A
Linan
Monica
M
Bakshi
Pancham
P
Ait-Ghezala
Ghania
G
Mullan
Michael
M
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
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