Alzheimer´s Disease (AD) is a neurodegenerative disorder due to accumulation of senile plaques made of amyloid b-peptides (Ab). Soluble, oligomeric species of Ab-peptides, rather than monomers of fibrils, are emerging as the cause of synaptic dysfunction and neuron death in AD. Disruption of neuronal Ca²⁺ signaling is involved in Ab-induced neurotoxicity. We show that oligomeric Ab1-42 and the toxic fragment Ab25-35 induces large, irreversible cytosolic Ca²⁺ increases in hypothalamic and cerebellar neurons that are followed by huge increases of mitochondrial Ca²⁺, as revealed by photon-counting imaging of mitochondria-targeted aequorin in single neurons. Ab induces also cytochrome c release, apoptosis and neuron cell death in the same neurons. We found that inhibition of mitochondrial Ca²⁺ uptake by the uncoupler FCCP prevented apoptosis and neuron cell death, thus revealing an important role of mitochondrial Ca²⁺ overload in Ab-induced neuron cell death.

Evidence indicate that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) protect against AD by a yet unknown mechanism. We show here that the aspirin metabolite salicylate and other NSAIDs prevent the Ab-induced release of cytochrome c and cell death. We also found that salicylate and other NSAIDs depolarize mitochondria and prevent the Ab-induced mitochondrial Ca²⁺ overload at the same concentrations. Taken together, our results suggest that i)Ab-induced neuron cell death depends largely on mitochondrial Ca²⁺ overload and ii)the neuroprotective effects of salicylate and other NSAIDs could be explained by their inhibitory effects on mitochondrial Ca²⁺ uptake. Supported by FIS PI04/1510 and Junta de Castilla y León VA022A05