Dysregulation of intracellular Ca²⁺ homeostasis may underlie amyloid b peptide (Ab) toxicity in Alzheimer's Disease (AD), but the mechanism is unknown.

Aim: 

Here, we investigate whether oligomers of Ab_1–42 induce a dyshomeostais in subcellular Ca²⁺ in hippocampal neurons as we have shown in cerebellar cells (1). In addition, we asked for possible pathways for deranged Ca²⁺ signals. Finally, we determined the role of mitochondrial Ca²⁺ uptake in neuron death induced by Ab_1–42 oligomers.

Methods: 

For these aims, we used fluorescence imaging of fura2 for monitoring cytosolic calcium and bioluminescence imaging of targeted aequorin for monitoring mitochondrial calcium in individual neurons.

Results: 

We found that Ab_1–42 oligomers, the assembly state correlating best with cognitive decline in AD, induce a massive entry of Ca²⁺ in hippocampal neurons promoting mitochondrial Ca²⁺ overload and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs) depolarize mitochondria and inhibit mitochondrial Ca²⁺ overload and cell death induced by Ab_1-42 oligomers. Moreover, we have used different calcium channel antagonists to ascertain the mechanism of Ca²⁺ entry. We found that the Ca²⁺ entry induced by Ab oligomers was prevented by NMDA receptor antagonists as well as amyloid channel blockers.

Conclusion: 

Our results indicate that: i)Ab_1-42 oligomers promote massive Ca²⁺ entry into hippocampal neurons most likely mediated by NMDA receptor. ii)Prevention of mitochondrial Ca²⁺ overload induced by Ab_1-42 oligomers may underlie neuroprotection provided by NSAIDs.

Funded FIS PI07/0766, BFU2006-05202 and Confederación de Cajas de Ahorros de Castilla y León, Spain.

1. Sanz-Blasco et al. (2008) Mitochondrial Ca²⁺ overload underlies Ab oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs. PLoS ONE. 3(7):e2718.