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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.

SUBMITTER: Calvo-Rodriguez M 

PROVIDER: S-EPMC7195480 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Calvo-Rodriguez Maria M   Hou Steven S SS   Snyder Austin C AC   Kharitonova Elizabeth K EK   Russ Alyssa N AN   Das Sudeshna S   Fan Zhanyun Z   Muzikansky Alona A   Garcia-Alloza Monica M   Serrano-Pozo Alberto A   Hudry Eloise E   Bacskai Brian J BJ  

Nature communications 20200501 1


Mitochondria contribute to shape intraneuronal Ca<sup>2+</sup> signals. Excessive Ca<sup>2+</sup> taken up by mitochondria could lead to cell death. Amyloid beta (Aβ) causes cytosolic Ca<sup>2+</sup> overload, but the effects of Aβ on mitochondrial Ca<sup>2+</sup> levels in Alzheimer's disease (AD) remain unclear. Using a ratiometric Ca<sup>2+</sup> indicator targeted to neuronal mitochondria and intravital multiphoton microscopy, we find increased mitochondrial Ca<sup>2+</sup> levels associated  ...[more]

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