Is it All Said for NSAI Ds in Alzheimer's Disease? Role of Mitochondrial Calcium Uptake

Objectives: Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including gamma-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid beta peptide (A beta). Methods: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. A beta oligomers promote Ca2+ influx and mitochondrial Cat' overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and R-flurbiprofen depolarize mitochondria in the low mu M range and prevent mitochondrial Ca2+ overload induced by A beta oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (Delta Psi) leading to cell death. Results: Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.