From the landmark epidemiological Rotterdam study in 2001 that- reported a 80% decrease in the risk of developing Alzheimer's disease (AD) in long-term users of non steroidal anti-inflammatory drugs (NSAIDs), to the recent failure of the ibuprofen derivative (R)-flurbiprofen in phase III of a clinical trial, the story of NSAIDs as therapeutics in AD has taken several unexpected turns. The key elusive question is the underlying target. It was initially considered to be cyclo-oxygenases, then the attention shifted to gamma secretase, and recent evidence suggests that Rho-GTPases should be brought into the spotlight. Additional important issues are the following: Is (R)-flurbiprofen defective despite the hype? Is the amyloid-cascade hypothesis wrong? Is the disease process too advanced in patients selected for clinical trials to allow for any improvement? Are NSAIDs just preventive? Why do some NSAIDs worsen the disease in patients? Is there any concealed bias in the analysis of epidemiological data that renders the conclusion wrong? Are NSAIDs like ibuprofen effective because they modulate several targets at once, that is, they are multifunctional, thus losing therapeutic potential when the capacity to inhibit one target is chemically enhanced at the expense of other actions? And, getting tough on inflammation and AD; what is really the role of reactive astrocytes and microglia in the disease? This Research Topic in Frontiers in Neuroscience is intended to critically discuss these questions to bring NSAID therapeutics in AD back on track.
Contributions:
Are NSAIDs useful to treat Alzheimer´s disease or mild cognitive impairment? Bruno Imbimbo, Chiesi Pharmaceutici, Parma, Italy. B.Imbimbo@chiesigroup.com
NSAIDs: a double edge sword in the treatment of Alzheimer's disease. Magdalena Sastre, Imperial College London. m.sastre@imperial.ac.uk
NSAIDs may protect against age-related brain atrophy. Barbara B. Bendlin. Winsonsin Alzheimer Research Center, University of Wisconsin, USA. bbb@medicine.wisc.edu
The nuclear receptor PPAR? as a therapeutic target for
cerebrovascular and brain dysfunction in Alzheimer's disease. Edith
Hamel, McGill University, Montreal, Canada. edith.hamel@mcgill.ca
Presenilins and brain inflammation. Carlos Saura. Universitat
Autònoma de Barcelona, Spain. carlos.saura@uab.cat
Microglial activation and neuroinflammation in Alzheimer's disease:
a critical examination of recent history. Wolfgang Streit. University
of Florida, USA. streit@mbi.ufl.edu
Conclusions and perspectives: Staging of anti-inflammatory treatment in Alzheimer´s disease. Mathieu Lichtenstein, Paulina Carriba, Roser Masgrau, Aurora Pujol, Elena Galea. Universitat Autónoma de Barcelona. Spain. In progress.
