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

• Published in: Nature communications Vol. 11; no. 1; p. 2146
• Main Authors: Calvo-Rodriguez, Maria, Hou, Steven S, Snyder, Austin C, Kharitonova, Elizabeth K, Russ, Alyssa N, Das, Sudeshna, Fan, Zhanyun, Muzikansky, Alona, Garcia-Alloza, Monica, Serrano-Pozo, Alberto, Hudry, Eloise, Bacskai, Brian J
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.05.2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Amyloidosis; Animals; Autopsy; Blotting, Western; Brain - metabolism; Calcium; Calcium (mitochondrial); Calcium - metabolism; Calcium efflux; Calcium imaging; Calcium influx; Calcium ions; Calcium signalling; Cell death; Cells, Cultured; Cytosol - metabolism; Deposition; Efflux; Gene expression; Gene sequencing; Genes; Immunohistochemistry; Male; Membrane Potential, Mitochondrial - physiology; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; Mortality; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Neurons - cytology; Neurons - metabolism; Oligomers; Overloading; Ribonucleic acid; RNA; Rodents; Therapeutic applications; Transgenic mice
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16074-2

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