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.