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Título
Amyloid β oligomers increase ER-mitochondria Ca2+ cross talk in young hippocampal neurons and exacerbate aging-induced intracellular Ca2+ remodeling
Autor
Año del Documento
2019
Editorial
Frontiers
Descripción
Producción Científica
Documento Fuente
Frontiers in Cellular Neuroscience, 2019, vol. 13. 18 p.
Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and strongly associated to aging. AD has been related to excess of neurotoxic oligomers of amyloid β peptide (Aβo), loss of intracellular Ca2+ homeostasis and mitochondrial damage. However, the intimate mechanisms underlying the pathology remain obscure. We have reported recently that long-term cultures of rat hippocampal neurons resembling aging neurons are prone to damage induced by Aβ oligomers (Aβo) while short-term cultured cells resembling young neurons are not. In addition, we have also shown that aging neurons display critical changes in intracellular Ca2+ homeostasis including increased Ca2+ store content and Ca2+ transfer from the endoplasmic reticulum (ER) to mitochondria. Aging also promotes the partial loss of store-operated Ca2+ entry (SOCE), a Ca2+ entry pathway involved in memory storage. Here, we have addressed whether Aβo treatment influences differentially intracellular Ca2+ homeostasis in young and aged neurons. We found that Aβo exacerbate the remodeling of intracellular Ca2+ induced by aging. Specifically, Aβo exacerbate the loss of SOCE observed in aged neurons. Aβo also exacerbate the increased resting cytosolic Ca2+ concentration, Ca2+ store content and Ca2+ release as well as increased expression of the mitochondrial Ca2+ uniporter (MCU) observed in aging neurons. In contrast, Aβo elicit none of these effects in young neurons. Surprisingly, we found that Aβo increased the Ca2+ transfer from ER to mitochondria in young neurons without having detrimental effects. Consistently, Aβo increased also colocalization of ER and mitochondria in both young and aged neurons. However, in aged neurons, Aβo suppressed Ca2+ transfer from ER to mitochondria, decreased mitochondrial potential, enhanced reactive oxygen species (ROS) generation and promoted apoptosis. These results suggest that modulation of ER—mitochondria coupling in hippocampal neurons may be a novel physiological role of Aβo. However, excess of Aβo in the face of the remodeling of intracellular Ca2+ homeostasis associated to aging may lead to loss of ER—mitochondrial coupling and AD.
Palabras Clave
Calcium
Calcio
Alzheimer’s disease
Enfermedad de Alzheimer
Aging
Envejecimento
Endoplasmic reticulum
Retículo endoplasmático
ISSN
1662-5102
Revisión por pares
SI
Patrocinador
Ministerio de Economía, Industria y Competitividad (grants BFU2012-37146 and BFU2015-70131R)
Junta de Castilla y León (grants VA145U13, BIO/VA33/13 and VA294P18)
Junta de Castilla y León (grants VA145U13, BIO/VA33/13 and VA294P18)
Version del Editor
Propietario de los Derechos
© 2019 Frontiers
Idioma
eng
Tipo de versión
info:eu-repo/semantics/publishedVersion
Derechos
openAccess
Collections
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