EFFECTS OF CADMIUM, COPPER, AND ZINC ON BETA-APP PROCESSING AND TURNOVER IN COS-7 AND PC12 CELLS - RELATIONSHIP TO ALZHEIMER-DISEASE PATHOLOGY

The effects of cadmium, copper, and zinc on beta APP metabolism were i nvestigated in COS-7 and PC12 cells. Cadmium chloride (CdCl2) increase d beta APP steady-state protein levels and decreased beta APP posttran slational processing. These changes were not accompanied by alteration s in beta APP mRNA levels or splicing. Ln addition, cytosolic alpha-ac tin and G3PDH levels were not affected. Further, neither zinc (ZnCl2) nor copper (CuSO4) altered beta APP levels or affected its normal proc essing. Pulse-chase studies revealed that the rate of beta APP maturat ion decreased twofold in the presence of 25 mu M CdCl2 compared to unt reated controls. beta APP secretion from the cell also dramatically sl owed. These two factors result in the accumulation of partially proces sed beta APP inside cells. The presence of CdCl2 also decreased the am ount of an 8-kDa beta APP C-terminal fragment, indicating that the cel lular compartment in which beta APP accumulates is not accessible to a lpha-secretase. Studies using Brefeldin A suggest that this compartmen t may be the cis or medial Golgi. However, A beta production was propo rtionately increased. These data show that CdCl2 can modulate the beta APP cleavage to favor A beta. Finally, beta APP mis-metabolism was sh own to be unrelated to the hsp70 induction elicited by CdCl2; both hea t shock and CuSO4 induced hsp70 but had no effect on steady-state leve ls of beta APP, although heat shock did slow beta APP maturation. Thes e data indicate that hsp70 alone cannot chaperone beta APP through an alternate processing pathway leading to A beta production.