Novel Mechanisms of NSAID Action in Alzheimer's Disease

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DESCRIPTION (provided by applicant): We have recently found that some non-steroidal anti-inflammatory drugs (NSAIDs) selectively decrease A?42 production by a mechanism that is independent of cyclooxygenase (COX) inhibition. Moreover, an independent study showed that chronic treatment with ibuprofen reduced A? deposition in a transgenic Alzheimer's disease (AD) mouse model. These data suggest that certain NSAIDs selectively reduce A?42, and that this effect rather than the COX mediated anti-inflammatory properties of these compounds might account for their apparent efficacy in reducing risk for AD. In order to explore this hypothesis the synthesis of novel compounds lacking COX activity yet maintaining the ability to lower A?42 is necessary. We have already identified several compounds that lack COX activity, lower A?42, and do so more potently than any of the FDA-approved NSAIDs. Moreover, we have identified a number of NSAID derivatives that unexpectedly raise A?42 and lower shorter A? derivatives including A?38. In addition, we have evidence that NSAIDs directly modulate gamma-secretase cleavage; therefore, we have begun to develop affinity reagents to identify the target responsible for the A?42 altering properties of these compounds. Finally, through systematic modification of several NSAIDs we have begun to identify important structure activity relationships (SAR) that are likely to result in the development of more potent and more selective A?42 lower agents. Based on these findings the aims of the chemical synthesis core are: 1) To produce large quantities of A?42 altering agents that are needed to conduct in vitro and in vivo studies outlined in Projects 1 and 2. 2) To synthesize affinity reagents derived from the A?42 altering agents that we have identified that can be used to identify the target responsible for the A?42 lowering effect of these compounds (Project 1). 3) To synthesize a series of molecules that will provide important information regarding the SAR of the A?42 altering agents. 4) Develop methods to enable detection and quantification of the level of these novel compounds in biological fluids and tissues.