Possible mechanisms of action of NSAIDs and related compounds that modulate gamma-secretase cleavage

Abstract

Genetic and biochemical evidence continues to implicate the production and accumulation of the Abeta42 peptide as the causative factor in Alzheimer's disease (AD). Thus, a variety of strategies have been developed to decrease the production and/or aggregation of this peptide, which may be clinically useful for the treatment of this devastating disorder. Recently, the discovery that some non-steroidal anti-inflammatory drugs (NSAIDs) appear to selectively decrease the production of Abeta42 has opened a novel therapeutic avenue for AD treatment that may circumvent potential toxicity associated with long-term global inhibition of gamma-secretase activity. One drug from this class of compounds, R-flurbiprofen, has advanced to phase 3 clinical trials and may soon provide insight into the viability of this strategy for the prevention or treatment of AD. Delineating the target and mechanism of these compounds is essential for developing new agents with increased potency and optimized pharmacologic properties. The evidence indicating that these chemicals modulate the production of Abeta peptides by directly interacting with the gamma-secretase complex is summarized.

Fig. 1

Some NSAIDs lower the secretion Ab42 from cell culture (A) or have no effect (B).

Fig. 2

Other NSAIDs that decrease Aβ42 in vitro and in vivo. The R- enantiomer of flurbiprofen is currently being tested in Phase III clinical trials for Alzheimer’s disease due to it’s ability to reduce Aβ42 and greatly reduced inhibition of COX.

Fig. 3

Compounds identified that mimic Familial-Alzheimer’s disease (FAD) mutations and elevate the production of Aβ42.

Fig. 4

Structural modification of idomethacin into a COX-2 selective inhibitor also creates a compound (LM4114) that now selectively raises Aβ42.

Fig. 5

Additional compounds identified that elevate Aβ42.