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

Maria Calvo-Rodriguez, Steven S. Hou, Austin C. Snyder, Elizabeth K. Kharitonova, Alyssa N. Russ, Sudeshna Das, Zhanyun Fan, Alona Muzikansky, Monica Garcia-Alloza, Alberto Serrano-Pozo, Eloise Hudry and Brian J. Bacskai ()
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Maria Calvo-Rodriguez: Massachusetts General Hospital and Harvard Medical School
Steven S. Hou: Massachusetts General Hospital and Harvard Medical School
Austin C. Snyder: Massachusetts General Hospital and Harvard Medical School
Elizabeth K. Kharitonova: Massachusetts General Hospital and Harvard Medical School
Alyssa N. Russ: Massachusetts General Hospital and Harvard Medical School
Sudeshna Das: Massachusetts General Hospital and Harvard Medical School
Zhanyun Fan: Massachusetts General Hospital and Harvard Medical School
Alona Muzikansky: Harvard School of Public Health
Monica Garcia-Alloza: Universidad de Cadiz
Alberto Serrano-Pozo: Massachusetts General Hospital and Harvard Medical School
Eloise Hudry: Massachusetts General Hospital and Harvard Medical School
Brian J. Bacskai: Massachusetts General Hospital and Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16074-2

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