Mechanism of amyloid beta-peptide (1-42) toxicity in PC12 cells.

Amyloid beta-peptide (A beta) deposition and loss of cholinergic neurons are characteristics of Alzheimer's disease. There is evidence that A beta is neurotoxic. The role of signal transduction pathways on A beta-induced toxicity in PC12 cells was investigated. Our results revealed that A beta-induced arachidonic acid was released in a time-dependent manner. Inhibitors of cyclooxygenase (1 microM indomethacin) and lipooxygenase (100 microM nordihydroguairetic acid) protected PC12 cells against 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-glycerol) and tacrine reversed A beta-induced toxicity. These results suggest that A beta toxicity can be modulated by manipulating signal transduction pathways and may provide the basis for novel therapeutic interventions.