Curcumin inhibits BACE1 expression through the interaction between ERβ and NFκB signaling pathway in SH-SY5Y cells.

Alzheimer's disease (AD) is the leading cause of dementia, which characterized by toxic senile plaques is composed of amyloid-β (Aβ). β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is the rate-limiting protease in Aβ generation. Therefore, pharmacology BACE1 inhibition is one of the prime targets for potential treatment of AD. Curcumin, a yellow polyphenol derived from the rhizomes of the plant Curcuma longa Linn, has been reported to cross the blood-brain barrier and prevent Aβ aggregation in AD models. However, its neuroprotective mechanism is still unclear. In the present study, we find that curcumin markedly reduces Aβ levels in HEK293-APPswe cells. Our results show that curcumin inhibits BACE1 gene expression in SH-SY5Y cells at transcriptional and translational levels. Furthermore, we reveal that nuclear factor kappa B (NFκB) signaling is involved in the regulation of curcumin on BACE1. Interestingly, the estrogenicity of curcumin is found to partially contribute to its protective action. Our data show that curcumin activates estrogen receptor β (ERβ) selectively and the activation of ERβ directly effects on the upstream factors of the NFκB signaling pathway. The above results indicate that curcumin reduces BACE1 expression through ERβ and NFκB pathway, providing a novel mechanism for curcumin as a candidate for AD therapy.