Nonsteroidal anti-inflammatory drugs (NSAIDs) and derived Aβ42-lowering molecules for treatment and prevention of Alzheimer's disease (AD)

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered for the treatment and prevention of Alzheimer's disease (AD) for more than two decades. The rationale for this approach is derived from epidemiological studies and from the observation that the causative amyloid pathology in the AD brain is accompanied by a secondary inflammatory response. Given that the primary pharmacological targets of NSAIDs are cyclooxygenases (COX), the reduced expression of inflammatory markers in AD mouse models after peripheral administration of NSAIDs has suggested that these compounds may be beneficial in AD by inhibiting a wide range of inflammatory responses in the central nervous system. Recent findings have shown that NSAIDs possess additional anti-amyloidogenic activities that provide an alternative explanation for their protective effects. Most notably, a subset of NSAIDs have been shown to selectively lower cellular production of the Aβ42 peptide, regarded by many to be the crucial disease-initiating agent. In contrast to conventional γ-secretase inhibitors, these Aβ42-lowering NSAIDs are γ-secretase modulators, as they block Aβ42 production without impairing the processing of other γ-secretase substrates. Importantly, the Aβ42-lowering activity of NSAIDs is not related to inhibition of COX and is separable from the anti-inflammatory properties of these compounds. In this chapter, we summarize the available evidence that the efficacy of NSAIDs in AD might be attributable to either anti-inflammatory or anti-amyloidogenic activities, and acknowledge the possibility that current NSAIDs could be particularly efficacious through a synergistic mechanism of action. Nevertheless, we propose that future drug development efforts should focus on the improvement of Aβ42-lowering molecules without COX activity, which could provide a potent means to prevent both amyloid pathology and secondary inflammatory reactions while avoiding clinical side effects associated with inhibition of COX and γ-secretase.