Inhibition of Aβ production by NF-κB inhibitors

The transcription factor nuclear factor κB (NF-κB) is widely expressed in the nervous system and increased NF-κB immunoreactivity has been observed in Alzheimer's disease (AD) brains in the nuclei of neurons within the vicinity of diffuse β-amyloid plaques. β-Amyloid (Aβ) peptides are the main constituent of senile plaques and are known to stimulate NF-κB activity. In the present study, we investigated the effect of various NF-κB inhibitors on the production of Aβ1–40, Aβ1–42, secreted APP (sAPPβ and sAPPα) and APP C-terminal fragments (APP-CTF) using CHO cells overexpressing the β-amyloid precursor protein (APP). Our data show that NF-κB inhibitors decrease both Aβ1–40 and Aβ1–42 production. In addition, we show that some NF-κB inhibitors decrease sAPPβ and APP-CTFβ suggesting that they reduce the β-secretase cleavage of APP. Altogether our data suggest that NF-κB 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 Aβ peptides.