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

Abstract

Mitochondria contribute to shape intraneuronal Ca²⁺ signals. Excessive Ca²⁺ taken up by mitochondria could lead to cell death. Amyloid beta (Aβ) causes cytosolic Ca²⁺ overload, but the effects of Aβ on mitochondrial Ca²⁺ levels in Alzheimer's disease (AD) remain unclear. Using a ratiometric Ca²⁺ indicator targeted to neuronal mitochondria and intravital multiphoton microscopy, we find increased mitochondrial Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ transporter genes, but upregulation in the genes related to mitochondrial Ca²⁺ efflux pathways, suggesting a counteracting effect to avoid Ca²⁺ overload. We propose lowering neuronal mitochondrial Ca²⁺ by inhibiting the mitochondrial Ca²⁺ uniporter as a novel potential therapeutic target against AD.