Molecular and Chemical Neuropathology

, Volume 31, Issue 1, pp 13–28 | Cite as

Effects of cadmium, copper, and zinc on βAPP processing and turnover in COS-7 and PC12 cells

Relationship to Alzheimer disease pathology
  • Marilyn Smedman
  • Anna Potempska
  • Richard Rubenstein
  • Weina Ju
  • Narayan Ramakrishna
  • Robert B. Denman
Original Articles
Received:
Revised:
Accepted:

Abstract

The effects of cadmium, copper, and zinc on βAPP metabolism were investigated in COS-7 and PC12 cells. Cadmium chloride (CdCl2) increased βAPP steady-state protein levels and decreased βAPP posttranslational processing. These changes were not accompanied by alterations in βAPP mRNA levels or splicing. In addition, cytosolic α-actin and G3PDH levels were not affected. Further, neither zinc (ZnCl2) nor copper (CuSO4) altered βAPP levels or affected its normal processing. Pulse-chase studies revealed that the rate of βAPP maturation decreased twofold in the presence of 25 μM CdCl2 compared to untreated controls. βAPP secretion from the cell also dramatically slowed. These two factors result in the accumulation of partially processed βAPP inside cells. The presence of CdCl2 also decreased the amount of an 8-kDa βAPP C-terminal fragment, indicating that the cellular compartment in which βAPP accumulates is not accessible to α-secretase. Studies using Brefeldin A suggest that this compartment may be thecis ormedial Golgi. However, Aβ production was proportionately increased. These data show that CdCl2 can modulate the βAPP cleavage to favor Aβ. Finally, βAPPmis-metabolism was shown to be unrelated to the hsp70 induction elicited by CdCl2; both heat shock and CuSO4 induced hsp70 but had no effect on steady-state levels of βAPP, although heat shock did slow βAPP maturation. These data indicate that hsp70 alone cannot chaperone βAPP through an alternate processing pathway leading to Aβ production.

Index Entries

βAPP Aβ secretase cadmium chloride zinc chloride copper sulfate hsp70 stress response Brefeldin A ROS reactive oxygen species amyloid 
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Copyright information

© Humana Press Inc 1997

Authors and Affiliations

  • Marilyn Smedman
    • 1
  • Anna Potempska
    • 1
  • Richard Rubenstein
    • 1
  • Weina Ju
    • 1
  • Narayan Ramakrishna
    • 1
  • Robert B. Denman
    • 1
  1. 1.New York State Institute for Basic Research in Developmental DisabilitiesStaten Island

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