טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentAvramovich-Tirosh Yael
SubjectThe Role of Inflammatory Processes in Neurodegeneration,
and Prospects for Neuroprotection with Anti-
inflammatory Drugs
DepartmentDepartment of Biotechnology
Supervisor Professor Emeritus Moussa Youdim


Abstract

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.