MECHANISM OF AMYLOID BETA-PEPTIDE(1-42) TOXICITY IN PC12 CELLS

Amyloid beta-peptide (A beta) deposition and loss of cholinergic neuro ns are characteristics of Alzheimer's disease. There is evidence that A beta is neurotoxic. The role of signal transduction pathways on A be ta-induced toxicity in PC12 cells was investigated. Our results reveal ed that A beta-induced arachidonic acid was released in a time-depende nt manner. Inhibitors of cyclooxygenase (1 mu M indomethacin) and lipo oxygenase (100 mu M nordihydroguairetic acid) protected PC12 cells aga inst A beta-induced toxicity. These data suggest that A beta toxicity is mediated by activation of the arachidonic acid cascade. Furthermore , protein kinase C activators (phorbol ester and 1-oleyl-2-acetyl-glyc erol) and tacrine reversed A beta-induced toxicity. These results sugg est that A beta toxicity can be modulated by manipulating signal trans duction pathways and may provide the basis for novel therapeutic inter ventions.