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

Authors :
Elizabeth K. Kharitonova
Alyssa N. Russ
Eloise Hudry
Alona Muzikansky
Austin Snyder
Sudeshna Das
Maria Calvo-Rodriguez
Monica Garcia-Alloza
Brian J. Bacskai
Zhanyun Fan
Alberto Serrano-Pozo
Steven S. Hou
Biomedicina, Biotecnología y Salud Pública
[Calvo-Rodriguez,M
Hou,SS
Snyder,AC
Kharitonova,EK
Russ,AN
Das,S
Fan,Z
Serrano-Pozo,A
Hudry,E
Bacskai,BJ] Department of Neurology, Massachusetts General Hospital and Harvard Medical School, MA, USA. [Muzikansky,A] Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA. [Garcia-Alloza,M] Division of Physiology, School of Medicine, Instituto de Investigacion Biomedica de Cadiz (INIBICA), Universidad de Cadiz, Cadiz, Spain.
This work was supported by NIHR01AG0442603, S10 RR025645 and R56AG060974 (BJB)
and by the Tosteson & Fund for Medical Discovery and the BrightFocus Foundation A2019488F (MCR). MSBB study was supported by the grants AG046170, AG054014, AG057440 and AG057907 from the NIH/National Institute on Aging (NIA). A.S.-P. was supported by the Alzheimer’s Association (AACF-17-524184) and the National Institute for Neurodegenerative Diseases and Stroke (NINDS R25NS065743).
Source :
Nature Communications (2020) 11:2146, RODIN. Repositorio de Objetos de Docencia e Investigación de la Universidad de Cádiz, instname, RODIN: Repositorio de Objetos de Docencia e Investigación de la Universidad de Cádiz, Universidad de Cádiz, Nature Communications, Vol 11, Iss 1, Pp 1-17 (2020)
Publication Year :
2020
Publisher :
NATURE PUBLISHING GROUP, 2020.

Abstract

Mitochondria contribute to shape intraneuronal Ca2+ signals. Excessive Ca2+ taken up by mitochondria could lead to cell death. Amyloid beta (A beta) causes cytosolic Ca2+ overload, but the effects of A beta 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 beta -amyloidosis. Naturally secreted soluble A beta 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. Calvo-Rodriguez et al. show elevated calcium levels in neuronal mitochondria in a mouse model of cerebral beta -amyloidosis after plaque deposition, which precede rare neuron death events in this model. The mechanism involves toxic extracellular A beta oligomers and the mitochondrial calcium uniporter.

Subjects

Subjects :
0301 basic medicine
Male
Plomo
General Physics and Astronomy
Mitochondrion
Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Immunologic Techniques::Immunohistochemistry [Medical Subject Headings]
Mice
0302 clinical medicine
Cytosol
Microscopía
Enfermedad de Alzheimer
Organisms::Eukaryota::Animals [Medical Subject Headings]
lcsh:Science
Anatomy::Nervous System::Neurons [Medical Subject Headings]
Cells, Cultured
Mitocondrias
Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Mitochondria [Medical Subject Headings]
Membrane Potential, Mitochondrial
Neurons
Microscopy
Multidisciplinary
biology
Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Molecular Probe Techniques::Blotting, Western [Medical Subject Headings]
Brain
Neurodegenerative Diseases
Immunohistochemistry
Cell biology
Mitochondria
Chemicals and Drugs::Inorganic Chemicals::Elements::Metals, Alkaline Earth::Calcium [Medical Subject Headings]
Encéfalo
Alzheimer disease
Neuron death
Genetically modified mouse
Cell death
Programmed cell death
Amyloid
Diseases::Nervous System Diseases::Neurodegenerative Diseases::Tauopathies::Alzheimer Disease [Medical Subject Headings]
Amyloid beta
Science
Blotting, Western
chemistry.chemical_element
Check Tags::Male [Medical Subject Headings]
Calcium
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Calcio
Diseases::Nervous System Diseases::Neurodegenerative Diseases [Medical Subject Headings]
Animals
Uniporter
Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytosol [Medical Subject Headings]
Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings]
Amiloide
Phenomena and Processes::Cell Physiological Phenomena::Membrane Potentials::Membrane Potential, Mitochondrial [Medical Subject Headings]
General Chemistry
Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings]
Muerte celular
Mice, Inbred C57BL
030104 developmental biology
chemistry
Genes
Lead
Anatomy::Cells::Cells, Cultured [Medical Subject Headings]
biology.protein
lcsh:Q
Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Laboratory::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred C57BL [Medical Subject Headings]
030217 neurology & neurosurgery

Details

Database :
OpenAIRE
Journal :
Nature Communications (2020) 11:2146, RODIN. Repositorio de Objetos de Docencia e Investigación de la Universidad de Cádiz, instname, RODIN: Repositorio de Objetos de Docencia e Investigación de la Universidad de Cádiz, Universidad de Cádiz, Nature Communications, Vol 11, Iss 1, Pp 1-17 (2020)
Accession number :
edsair.doi.dedup.....e26b55b79ff36c7a4f5e2e60b93236be