Previous studies have demonstrated that
amyloid precursor
protein (APP) can bind and reduce Cu(II) to Cu(I), leading to oxidative modification of APP. In the present study we show that adding
copper to Chinese-hamster ovary (CHO) cells greatly reduced the levels of
amyloid Abeta
peptide (Abeta) 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 Abeta release was not due to a general inhibition in
protein secretion. There was an increase in intracellular full-length APP levels which paralleled the decrease in Abeta generation, suggesting the existence of two distinct regulating mechanisms, one acting on Abeta production and the other on APP synthesis. Maximal inhibition of Abeta production and stimulation of APP secretion was achieved in CHO-K1 cells at about 10 microM
copper and in CHO-CUR3 cells at about 50 microM
copper. This dose 'window of opportunity' at which
copper promoted the non-amyloidogenic pathway of APP was confirmed 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.