Figure 9. A model of Aβ-induced toxicity and neuroprotection by NSAIDs based on mitochondrial Ca²⁺.

Aβ_1–42 oligomers and the toxic fragment Aβ_25–35 induce a large entry of Ca²⁺ through the plasma membrane likely mediated by formation of amyloid channels and/or NMDA receptors. This entry promotes in a sequential manner mitochondrial Ca²⁺ overload, ROS production, mPTP opening, cytochrome c release, apoptosis and cell death. Other factors related to AD may favor mitochondrial Ca²⁺ overload including exaggerated IP₃-induced release of Ca²⁺ from the ER in loss of function PS1 mutants related to familial AD and/or decreased abundance of endogenous Ca²⁺ buffers as calbindinD28k during aging or sporadic AD. NSAIDs, at low concentrations (1 µM), depolarize partially mitochondria and inhibit mitochondrial Ca²⁺ overload, thus preventing cytochrome c release and apoptosis induced by Aβ oligomers.