Title:Is it All Said for NSAIDs in Alzheimer’s Disease? Role of Mitochondrial Calcium Uptake
Volume: 15
Issue: 6
Author(s): Sara Sanz-Blasco, Maria Calvo-Rodríguez, Erica Caballero, Monica Garcia-Durillo, Lucia Nunez and Carlos Villalobos*
Affiliation:
- Institute of Molecular Biology and Genetics (IBGM), National Research Council of Spain (CSIC), Valladolid,Spain
Keywords:
Alzheimer's disease, non-steroidal anti-inflammatory drugs, calcium, mitochondria, amyloid β oligomers,
N-methyl-D-aspartate.
Abstract: 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 γ-secretase that cleaves the amyloid precursor protein (APP) and yields
amyloid β peptide (Aβ).
Methods: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial
Ca2+ overload. Aβ oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to
neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen
depolarize mitochondria in the low µM range and prevent mitochondrial Ca2+ overload induced
by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations,
NSAIDs may collapse mitochondrial potential (ΔΨ) 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.
