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Remodeling of Intracellular Ca2+ Homeostasis in Rat Hippocampal Neurons Aged In Vitro

1
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
2
Institute of Biology and Molecular Genetics (IBGM), University of Valladolid and National Research Council (CSIC), 47003 Valladolid, Spain
3
Faculty of Odontology, Complutense University of Madrid, 28040 Madrid, Spain
4
Department of Biochemistry and Molecular Biology and Physiology, University of Valladolid, 47005 Valladolid, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(4), 1549; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041549
Received: 1 February 2020 / Revised: 19 February 2020 / Accepted: 20 February 2020 / Published: 24 February 2020
Aging is often associated with a cognitive decline and a susceptibility to neuronal damage. It is also the most important risk factor for neurodegenerative disorders, particularly Alzheimer’s disease (AD). AD is related to an excess of neurotoxic oligomers of amyloid β peptide (Aβo); however, the molecular mechanisms are still highly controversial. Intracellular Ca2+ homeostasis plays an important role in the control of neuronal activity, including neurotransmitter release, synaptic plasticity, and memory storage, as well as neuron cell death. Recent evidence indicates that long-term cultures of rat hippocampal neurons, resembling aged neurons, undergo cell death after treatment with Aβo, whereas short-term cultures, resembling young neurons, do not. These in vitro changes are associated with the remodeling of intracellular Ca2+ homeostasis with aging, thus providing a simplistic model for investigating Ca2+ remodeling in aging. In vitro aged neurons show increased resting cytosolic Ca2+ concentration, enhanced Ca2+ store content, and Ca2+ release from the endoplasmic reticulum (ER). Ca2+ transfer from the endoplasmic reticulum (ER) to mitochondria is also enhanced. Aged neurons also show decreased store-operated Ca2+ entry (SOCE), a Ca2+ entry pathway related to memory storage. At the molecular level, in vitro remodeling is associated with changes in the expression of Ca2+ channels resembling in vivo aging, including changes in N-methyl-D-aspartate NMDA receptor and inositol 1,4,5-trisphosphate (IP3) receptor isoforms, increased expression of the mitochondrial calcium uniporter (MCU), and decreased expression of Orai1/Stim1, the molecular players involved in SOCE. Additionally, Aβo treatment exacerbates most of the changes observed in aged neurons and enhances susceptibility to cell death. Conversely, the solely effect of Aβo in young neurons is to increase ER–mitochondria colocalization and enhance Ca2+ transfer from ER to mitochondria without inducing neuronal damage. We propose that cultured rat hippocampal neurons may be a useful model to investigate Ca2+ remodeling in aging and in age-related neurodegenerative disorders. View Full-Text
Keywords: calcium; hippocampal neurons; aging; Alzheimer’s disease; amyloid beta oligomers; endoplasmic reticulum; mitochondria calcium; hippocampal neurons; aging; Alzheimer’s disease; amyloid beta oligomers; endoplasmic reticulum; mitochondria
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MDPI and ACS Style

Calvo-Rodriguez, M.; Hernando-Pérez, E.; López-Vázquez, S.; Núñez, J.; Villalobos, C.; Núñez, L. Remodeling of Intracellular Ca2+ Homeostasis in Rat Hippocampal Neurons Aged In Vitro. Int. J. Mol. Sci. 2020, 21, 1549. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041549

AMA Style

Calvo-Rodriguez M, Hernando-Pérez E, López-Vázquez S, Núñez J, Villalobos C, Núñez L. Remodeling of Intracellular Ca2+ Homeostasis in Rat Hippocampal Neurons Aged In Vitro. International Journal of Molecular Sciences. 2020; 21(4):1549. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041549

Chicago/Turabian Style

Calvo-Rodriguez, Maria, Elena Hernando-Pérez, Sara López-Vázquez, Javier Núñez, Carlos Villalobos, and Lucía Núñez. 2020. "Remodeling of Intracellular Ca2+ Homeostasis in Rat Hippocampal Neurons Aged In Vitro" International Journal of Molecular Sciences 21, no. 4: 1549. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041549

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