Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer's disease.
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| 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.
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| Authors | 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, Brian J Bacskai |
| Journal | Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 2146 (05 01 2020) ISSN: 2041-1723 [Electronic] England |
| PMID | 32358564 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
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