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.