Copper inhibits beta-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) bo th in parental CHO-K1 and in copper-resistant CHO-CUR3 cells, which have lo wer intracellular copper levels, Copper also caused an increase in the secr etion of the APP ectodomain, indicating that the large decrease in A beta r elease was not due to a general inhibition in protein secretion. Then was a n increase in intracellular full-length APP levels which paralleled the dec rease in A beta generation, suggesting the existence of two distinct regula ting mechanisms, one acting on A beta production and the other on APP synth esis. Maximal inhibition of A beta production and stimulation of APP secret ion was achieved in CHO-KI cells at about 10 mu M copper and in CHO-CUR3 ce lls at about 50 mu M copper. This dose 'window of opportunity' at which cop per promoted the non-amyloidogenic pathway of APP was contirmed by an incre ase in the non-amyloidogenic p3 fragment produced by alpha-secretase cleava ge, Our findings suggest that copper or copper agonists might be useful too ls to discover novel targets for anti-Alzheimer drugs and may prove benefic ial for the prevention of Alzheimer's disease.