2 results on '"Hudry E"'
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2. Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer's disease
- Author
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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 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).
- 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 - 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.
- Published
- 2020
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