The potential role of non-steroidal anti-inflammatory drugs in treating Alzheimer’s disease

Abstract

Epidemiological studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Despite encouraging evidence, all large, long-term, placebo-controlled clinical trials aimed at reducing inflammation in the brain of AD patients produced negative results. More recently it has been shown that some NSAIDs decrease the production of amyloid-β_1-42 (Aβ42), the major component of senile plaques of the AD brain, and counteract the progression of Aβ42 pathology in transgenic mouse models of AD. The proposed mechanism for this activity is an allosteric modulation of γ-secretase activity, the enzyme responsible for the formation of amyloid-β. The inhibition of Aβ42 production is independent from the anti-cyclooxygenase (COX) activity and is related to the chemical structure of the compounds, with some NSAIDs being active (ibuprofen, sulindac, flurbiprofen, indomethacin, diclofenac) and others not (naproxen, aspirin, celecoxib). This could explain the negative results of the large AD trials carried out so far, as they were conducted with compounds (naproxen, hydroxychloroquine, dapsone, prednisone, rofecoxib and celecoxib) that are not able to decrease Aβ42 production. Unfortunately, the use of these NSAIDs in AD is hampered by a significant gastrointestinal toxicity associated with COX inhibition. Thus, new NSAID analogues are being developed with potent and selective inhibitory activity on Aβ42 but with either lack of COX inhibitory activity or reduced gastrointestinal toxicity potential.

• Alzheimer’s disease
• amyloid-β
• γ-secretase
• non-steroidal anti-inflammatory drugs