Increased reactive oxygen species (ROS) generation and the ensuing oxidative stress contribute to Alzheimer’s disease pathology. We reported previously that amyloid-Î² peptide oligomers (AÎ²Os) produce aberrant Ca2+ signals at sublethal concentrations and decrease the expression of type-2 ryanodine receptors (RyR2), which are crucial for hippocampal synaptic plasticity and memory. Here, we investigated whether the antioxidant agent astaxanthin (ATX) protects neurons from AÎ²Os-induced excessive mitochondrial ROS generation, NFATc4 activation, and RyR2 mRNA downregulation. To determine mitochondrial H2O2 production or NFATc4 nuclear translocation, neurons were transfected with plasmids coding for HyperMito or NFATc4-eGFP, respectively. Primary hippocampal cultures were incubated with 0.1”‰Î¼M ATX for 1.5”‰h prior to AÎ²Os addition (500”‰nM). We found that incubation with ATX (â‰¤10”‰Î¼M) for â‰¤24”‰h was nontoxic to neurons, evaluated by the live/dead assay. Preincubation with 0.1”‰Î¼M ATX also prevented the neuronal mitochondrial H2O2 generation induced within minutes of AÎ²Os addition. Longer exposures to AÎ²Os (6”‰h) promoted NFATc4-eGFP nuclear translocation and decreased RyR2 mRNA levels, evaluated by detection of the eGFP-tagged fluorescent plasmid and qPCR, respectively. Preincubation with 0.1”‰Î¼M ATX prevented both effects. These results indicate that ATX protects neurons from the noxious effects of AÎ²Os on mitochondrial ROS production, NFATc4 activation, and RyR2 gene expression downregulation.