Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease

Mitochondria contribute to shape intraneuronal Ca 2+ signals. Excessive Ca 2+ taken up by mitochondria could lead to cell death. Amyloid beta (Aβ) causes cytosolic Ca 2+ overload, but the effects of Aβ on mitochondrial Ca 2+ levels in Alzheimer’s disease (AD) remain unclear. Using a ratiometric Ca 2+ indicator targeted to neuronal mitochondria and intravital multiphoton microscopy, we find increased mitochondrial Ca 2+ levels associated with plaque deposition and neuronal death in a transgenic mouse model of cerebral β-amyloidosis. Naturally secreted soluble Aβ applied onto the healthy brain increases Ca 2+ concentration in mitochondria, which is prevented by blockage of the mitochondrial calcium uniporter. RNA-sequencing from post-mortem AD human brains shows downregulation in the expression of mitochondrial influx Ca 2+ transporter genes, but upregulation in the genes related to mitochondrial Ca 2+ efflux pathways, suggesting a counteracting effect to avoid Ca 2+ overload. We propose lowering neuronal mitochondrial Ca 2+ by inhibiting the mitochondrial Ca 2+ uniporter as a novel potential therapeutic target against AD.