|M.Sc Student||Avramovich-Tirosh Yael|
|Subject||The Role of Inflammatory Processes in Neurodegeneration,|
and Prospects for Neuroprotection with Anti-
|Department||Department of Biotechnology||Supervisor||Professor Emeritus Moussa Youdim|
Chronic inflammatory processes are associated with the pathophysiology of Alzheimer’s disease (AD) and it has been proposed that treatment of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk for AD. Here we report that various NSAIDs, such as the cyclooxygenase (COX) inhibitors: nimesulide (Nim), ibuprofen and indomethacin, as well as thalidomide (Thal) and its non-teratogenic analogue, supidimide significantly stimulated the secretion of the non-amyloidogenic a-secretase form of the soluble amyloid precursor protein (sAPPa) into the conditioned media of SH-SY5Y neuroblastoma and PC12 cells. Enhanced sAPP secretion was observed by two types of monoclonal antibodies: 22C11 (recognizes the N- terminus of APP), and 6E10 (recognizes an epitope within residues1-17 of the Ab domain of APP); therefore, the identified bands can be assumed to be a-secretase-cleaved form of sAPP. In support, the hydroxiamic acid-based inhibitor, Ro31-9790, was used. Since a-secretase is a zinc metalloproteinase, the effect of Ro31-9790, on Nim-, Thal-, or Sup- mediated sAPP release was examined. Ro31-9790, inhibited the constitutive as well the induced sAPP secretion, suggesting a direct involvement of a-secretase on APP processing.
These NSAIDs markedly reduced the levels of the cellular APP holoprotein, further accelerating non-amyloidogenic processes. sAPPa release, induced by Nim and Thal, was modulated by inhibitors of protein kinase C and Erk 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 a- secretase activity, thereby reducing the formation of amyloidogenic derivatives, and therefore are of potential therapeutic value in AD.