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.
Fagarasan
M O
MO
Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
Efthimiopoulos
S
S
D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004075:Diglycerides / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D009637:Masoprocol / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects* / Q000201:enzymology; D010277:Parasympathomimetics / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013619:Tacrine / Q000494:pharmacology; D013997:Time Factors
D016229:Amyloid beta-Peptides; D002273:Carcinogens; D016861:Cyclooxygenase Inhibitors; D004075:Diglycerides; D018696:Neuroprotective Agents; D010277:Parasympathomimetics; D010703:Phorbol Esters; D016718:Arachidonic Acid; D013619:Tacrine; D009637:Masoprocol; C038237:1-oleoyl-2-acetylglycerol; D002217:Carbachol; D011493:Protein Kinase C; D007213:Indomethacin