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Remodeling of Intracellular Ca(2+) Homeostasis in Rat Hippocampal Neurons Aged In Vitro

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 mo...

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Autores principales: Calvo-Rodriguez, Maria, Hernando-Pérez, Elena, López-Vázquez, Sara, Núñez, Javier, Villalobos, Carlos, Núñez, Lucía
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073228/
https://www.ncbi.nlm.nih.gov/pubmed/32102482
http://dx.doi.org/10.3390/ijms21041549
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author Calvo-Rodriguez, Maria
Hernando-Pérez, Elena
López-Vázquez, Sara
Núñez, Javier
Villalobos, Carlos
Núñez, Lucía
author_facet Calvo-Rodriguez, Maria
Hernando-Pérez, Elena
López-Vázquez, Sara
Núñez, Javier
Villalobos, Carlos
Núñez, Lucía
author_sort Calvo-Rodriguez, Maria
collection PubMed
description 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 Ca(2+) 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 Ca(2+) homeostasis with aging, thus providing a simplistic model for investigating Ca(2+) remodeling in aging. In vitro aged neurons show increased resting cytosolic Ca(2+) concentration, enhanced Ca(2+) store content, and Ca(2+) release from the endoplasmic reticulum (ER). Ca(2+) transfer from the endoplasmic reticulum (ER) to mitochondria is also enhanced. Aged neurons also show decreased store-operated Ca(2+) entry (SOCE), a Ca(2+) entry pathway related to memory storage. At the molecular level, in vitro remodeling is associated with changes in the expression of Ca(2+) channels resembling in vivo aging, including changes in N-methyl-D-aspartate NMDA receptor and inositol 1,4,5-trisphosphate (IP(3)) 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 Ca(2+) transfer from ER to mitochondria without inducing neuronal damage. We propose that cultured rat hippocampal neurons may be a useful model to investigate Ca(2+) remodeling in aging and in age-related neurodegenerative disorders.
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spelling pubmed-70732282020-03-19 Remodeling of Intracellular Ca(2+) Homeostasis in Rat Hippocampal Neurons Aged In Vitro Calvo-Rodriguez, Maria Hernando-Pérez, Elena López-Vázquez, Sara Núñez, Javier Villalobos, Carlos Núñez, Lucía Int J Mol Sci Review 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 Ca(2+) 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 Ca(2+) homeostasis with aging, thus providing a simplistic model for investigating Ca(2+) remodeling in aging. In vitro aged neurons show increased resting cytosolic Ca(2+) concentration, enhanced Ca(2+) store content, and Ca(2+) release from the endoplasmic reticulum (ER). Ca(2+) transfer from the endoplasmic reticulum (ER) to mitochondria is also enhanced. Aged neurons also show decreased store-operated Ca(2+) entry (SOCE), a Ca(2+) entry pathway related to memory storage. At the molecular level, in vitro remodeling is associated with changes in the expression of Ca(2+) channels resembling in vivo aging, including changes in N-methyl-D-aspartate NMDA receptor and inositol 1,4,5-trisphosphate (IP(3)) 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 Ca(2+) transfer from ER to mitochondria without inducing neuronal damage. We propose that cultured rat hippocampal neurons may be a useful model to investigate Ca(2+) remodeling in aging and in age-related neurodegenerative disorders. MDPI 2020-02-24 /pmc/articles/PMC7073228/ /pubmed/32102482 http://dx.doi.org/10.3390/ijms21041549 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Calvo-Rodriguez, Maria
Hernando-Pérez, Elena
López-Vázquez, Sara
Núñez, Javier
Villalobos, Carlos
Núñez, Lucía
Remodeling of Intracellular Ca(2+) Homeostasis in Rat Hippocampal Neurons Aged In Vitro
title Remodeling of Intracellular Ca(2+) Homeostasis in Rat Hippocampal Neurons Aged In Vitro
title_full Remodeling of Intracellular Ca(2+) Homeostasis in Rat Hippocampal Neurons Aged In Vitro
title_fullStr Remodeling of Intracellular Ca(2+) Homeostasis in Rat Hippocampal Neurons Aged In Vitro
title_full_unstemmed Remodeling of Intracellular Ca(2+) Homeostasis in Rat Hippocampal Neurons Aged In Vitro
title_short Remodeling of Intracellular Ca(2+) Homeostasis in Rat Hippocampal Neurons Aged In Vitro
title_sort remodeling of intracellular ca(2+) homeostasis in rat hippocampal neurons aged in vitro
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073228/
https://www.ncbi.nlm.nih.gov/pubmed/32102482
http://dx.doi.org/10.3390/ijms21041549
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