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Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease
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Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease
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Journal Article
Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease
2020
Overview
Mitochondria contribute to shape intraneuronal Ca
2+
signals. Excessive Ca
2+
taken up by mitochondria could lead to cell death. Amyloid beta (Aβ) causes cytosolic Ca
2+
overload, but the effects of Aβ on mitochondrial Ca
2+
levels in Alzheimer’s disease (AD) remain unclear. Using a ratiometric Ca
2+
indicator targeted to neuronal mitochondria and intravital multiphoton microscopy, we find increased mitochondrial Ca
2+
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
2+
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
2+
transporter genes, but upregulation in the genes related to mitochondrial Ca
2+
efflux pathways, suggesting a counteracting effect to avoid Ca
2+
overload. We propose lowering neuronal mitochondrial Ca
2+
by inhibiting the mitochondrial Ca
2+
uniporter as a novel potential therapeutic target against AD.
Calvo-Rodriguez et al. show elevated calcium levels in neuronal mitochondria in a mouse model of cerebral β-amyloidosis after plaque deposition, which precede rare neuron death events in this model. The mechanism involves toxic extracellular Aβ oligomers and the mitochondrial calcium uniporter.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/1
/ 13/106
/ 13/2
/ 13/51
/ 14/19
/ 14/33
/ 14/34
/ 14/35
/ 14/69
/ 64/110
/ 64/60
/ Alzheimer Disease - metabolism
/ Animals
/ Autopsy
/ Calcium
/ Efflux
/ Genes
/ Humanities and Social Sciences
/ Male
/ Membrane Potential, Mitochondrial - physiology
/ Mice
/ Neurodegenerative Diseases - metabolism
/ RNA
/ Rodents
/ Science
