Non-steroidal anti-inflammatory drugs stimulate secretion of non-amyloidogenic precursor protein.
Chronic inflammatory processes are associated with the pathophysiology of Alzheimer's disease (AD), and it has been proposed that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk for AD. Here we report that various NSAIDs, such as the cyclooxygenase inhibitors, nimesulide, ibuprofen and indomethacin, as well as thalidomide (Thal) and its non-teratogenic analogue, supidimide, significantly stimulated the secretion of the non-amyloidogenic alpha-secretase form of the soluble amyloid precursor protein (sAPP alpha) into the conditioned media of SH-SY5Y neuroblastoma and PC12 cells. These NSAIDs markedly reduced the levels of the cellular APP holoprotein, further accelerating non-amyloidogenic processes. sAPP alpha release, induced by nimesulide and Thal, was modulated by inhibitors of protein kinase C and Erk mitogen-activated protein (MAP) kinase. Furthermore, in results complementary to the inhibitor studies, we show for the first time that NSAIDs can activate the Erk MAP kinase signaling cascade, thus identifying a novel pharmacology mechanism of NSAIDs. Our findings suggest that NSAIDs and Thal might prove useful to favor non-amyloidogenic APP processing by enhancing alpha-secretase activity, thereby reducing the formation of amyloidogenic derivatives, and therefore are of potential therapeutic value in AD.
Avramovich
Yael
Y
Eve Topf and National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Technion - Faculty of Medicine, 31096 Haifa, Israel.
Amit
Tamar
T
Youdim
Moussa B H
MB
D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism; D016716:PC12 Cells; D010673:Pheochromocytoma; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D013792:Thalidomide / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D013449:Sulfonamides; D013792:Thalidomide; D020928:Mitogen-Activated Protein Kinases; C012655:nimesulide; D007052:Ibuprofen; D007213:Indomethacin