Decrease of Amyloid-β Levels by Curcumin Derivative via Modulation of Amyloid-β Protein Precursor Trafficking

The abnormal production and deposition of amyloid-beta (A beta) peptides is a pathologic hallmark of Alzheimer's disease. A beta is generated from amyloid-beta protein precursor (A beta PP) by two sequential proteolytic cleavage steps involving beta- and gamma-secretases in the trans-Golgi network and endosomes. Since direct inhibition of secretase could induce undesirable side-effects due to inadvertent inhibition of unrelated secretase substrates, it is important to establish methods for inhibiting A beta production that do not affect secretase activity. It has been suggested that curcumin may have potent anti-amyloidogenic effect. In the present study, we evaluate the effect of curcumin derivatives on A beta production in human neuroblastoma SH-SY5Y cells and in CHO cells which stably express human A beta PP (CHO-A beta PP). We found that the curcumin derivative CU6 was more effective than curcumin itself in reducing A beta secretion. We further found that in SH-SY5Y cells CU6 inhibited neither beta- nor gamma-secretase activity, and that increased amounts of immature forms of A beta PP accumulated in the endoplasmic reticulum (ER). We also found that CU6 induced expression of the ER chaperone glucose-regulated protein 78 (GRP78), and enhanced formation of the A beta PP/GRP78 complex. These results suggest that CU6 downregulates intracellular A beta PP trafficking, resulting in suppression of A beta production independently of secretase activity.