Copper inhibits β-amyloid production and stimulates the non-amyloidogenic pathway of amyloid-precursor-protein secretion

Previous studies have demonstrated that amyloid precursor protein (APP) can bind and reduce Cu(II) to Cu(I), leading to oxidative modification of APP, Ln the present study we show that adding copper to Chinese-hamster ovary (CHO) cells greatly reduced the levels of amyloid A beta peptide (A beta) both in parental CHO-K1 and in copper-resistant CHO-CUR3 cells, which have lower intracellular copper levels, Copper also caused an increase in the secretion of the APP ectodomain, indicating that the large decrease in A beta release was not due to a general inhibition in protein secretion. Then was an increase in intracellular full-length APP levels which paralleled the decrease in A beta generation, suggesting the existence of two distinct regulating mechanisms, one acting on A beta production and the other on APP synthesis. Maximal inhibition of A beta production and stimulation of APP secretion was achieved in CHO-KI cells at about 10 mu M copper and in CHO-CUR3 cells at about 50 mu M copper. This dose 'window of opportunity' at which copper promoted the non-amyloidogenic pathway of APP was contirmed by an increase in the non-amyloidogenic p3 fragment produced by alpha-secretase cleavage, Our findings suggest that copper or copper agonists might be useful tools to discover novel targets for anti-Alzheimer drugs and may prove beneficial for the prevention of Alzheimer's disease.