Molecular Mechanisms and Therapeutic Application of NSAIDs and Derived Compounds in Alzheimers Disease

M.      T. Heneka; M.      P. Kummer; S.      Weggen; B.      Bulic; G.      Multhaup; L.      Munter; M.      Hull; T.      Pflanzner; C.      U. Pietrzik

Abstract

Alzheimers disease (AD) is the most common form of neurodegenerative dementias worldwide. Amyloid-β deposition, neurofibrillary tangle formation and Neuroinflammation are the major pathogenetic mechanisms that in concert lead to memory dysfunction and decline of cognition. To date, there is no curative treatment for AD. Epidemiological analysis support the notion that sustained intake of non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk and delay the onset of AD. In contrast, therapeutic studies testing NSAID efficacy in AD patients have not yielded positive results. This suggests that either the investigated drugs have not addressed the mechanism of action required for mediating beneficial effects or that NSAIDs are effective at stages way before clinical onset of symptoms. The NSAIDs concerned are pleiotrophic in nature and interact with more than one pathomechanism. Therefore evidence for more than one neuroprotective action of NSAIDs has been put forward and it seems likely that some of the drugs act at multiple levels through more than one molecular mechanism. Some, even may not only be beneficial, but negative actions may be overruled by protective effects. Within these mechanisms, modulation of γ-secretase activity, the activation of the peroxisome proliferator- activated receptor-γ, binding to prostaglandin receptors or interactions at the blood-brain barrier may account for the observed protection from AD. This article reviews the current knowledge and views on the above mechanisms and critically discusses current obstacles and the potential as future AD therapeutics.

Keywords: Alzheimer's disease, amyloid-β, blood-brain barrier, transmembrane receptor, ABC transporter, clearance, nuclear hormone receptor, peroxisome proliferator activated receptor, nonsteroidal anti-inflammatory drug, γ-secretase modulation,