REVIEW Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer’s disease: old and new mechanisms of action

Alzheimer’s disease (AD) is characterized by cerebral deposits of b-amyloid (Ab) peptides and neurofibrillary tangles (NFT) which are surrounded by inflammatory cells. Epidemiological studies have shown that prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays the onset of the disease. It has been postulated that some NSAIDs target pathological hallmarks of AD by interacting with several pathways, including the inhibition of cyclooxygenases (COX) and activation of the peroxisome proliferator-activated receptor c. A variety of experimental studies indicate that a subset of NSAIDs such as ibuprofen, flurbiprofen, indomethacin and sulindac also possess Ab-low-ering properties in both AD transgenic mice and cell cultures of peripheral, glial and neuronal origin. While COX inhibition oc-curs at low concentrations in vitro (nM-low lM range), the Ab-lowering activity is observed at high concentrations ( £ 50 lM). Nonetheless, studies with flurbiprofen or ibuprofen in AD transgenic mice show that the effects on Ab levels or deposition are attained at plasma levels similar to those achieved in humans at therapeutic dosage. Still, it remains to be assessed whether adequate concentrations are reached in the brain. This is a crucial aspect that will allow defining the dose-window and the length of treatment in future clinical tri-als. Here, we will discuss how the combination of anti-amy-loidogenic and anti-inflammatory activities of certain NSAIDs may produce a profile potentially relevant to their clinical use as disease-modifying agents for the treatment of AD