Amyloid β Oligomers Increase ER-Mitochondria Ca2+ Cross Talk in Young Hippocampal Neurons and Exacerbate Aging-Induced Intracellular Ca2+ Remodeling

Calvo-Rodríguez, María; Hernando-Pérez, Elena; Núñez, Lucía González; Alonso, Carlos

doi:10.3389/fncel.2019.00022

Cited by 91 publications

(76 citation statements)

References 75 publications

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“…These oscillations can be abolished by tetrodotoxin, indicating they are dependent on synaptic network communication among neurons. However, after several weeks in vitro, the neuronal cultures lose this ability and show increased resting levels of intracellular Ca 2+ concentration relative to the short-term cultures instead [38]. Chronic exposure of rat hippocampal neurons to Aβo for 24 h has no effect on synchronic cytosolic Ca 2+ oscillations.…”

Section: Remodeling Of Intracellular Ca 2+ and Store-operated Ca 2+ Ementioning

confidence: 92%

“…Chronic exposure of rat hippocampal neurons to Aβo for 24 h has no effect on synchronic cytosolic Ca 2+ oscillations. Intriguingly, in aged neurons, Aβo treatment resumes synchronic oscillations [38]. Ca 2+ hyperactivity has also been shown in in vivo mouse models of cerebral amyloidosis [39].…”

Section: Remodeling Of Intracellular Ca 2+ and Store-operated Ca 2+ Ementioning

confidence: 98%

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

Calvo-Rodríguez

Hernando-Pérez

López-Vázquez

et al. 2020

IJMS

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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.

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Section: Remodeling Of Intracellular Ca 2+ and Store-operated Ca 2+ Ementioning

confidence: 92%

Section: Remodeling Of Intracellular Ca 2+ and Store-operated Ca 2+ Ementioning

confidence: 98%

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

Calvo-Rodríguez

Hernando-Pérez

López-Vázquez

et al. 2020

IJMS

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“…Abramov et al (2004a) identified that Aβ causes Ca 2+ -dependent oxidative stress by the activation of NADPH oxidase in astrocytes and that the reduced antioxidant activity induces neuronal death. Recently, Calvo-Rodriguez et al (2019) suggested that Aβ oligomers exacerbate Ca 2+ remodeling from ER to mitochondria in aged neurons but not in young neurons. Conversely, Itkin et al (2011) argued that Ca 2+ stimulates the formation of Aβ oligomers, leading to neuronal toxicity in AD.…”

Section: The Critical Role Of Ca 2+ In the Pathogenesis Of Neurodegenmentioning

confidence: 99%

TRP Channels as Emerging Therapeutic Targets for Neurodegenerative Diseases

et al. 2020

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The development of treatment for neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis is facing medical challenges due to the increasingly aging population. However, some pharmaceutical companies have ceased the development of therapeutics for NDs, and no new treatments for NDs have been established during the last decade. The relationship between ND pathogenesis and risk factors has not been completely elucidated. Herein, we review the potential involvement of transient receptor potential (TRP) channels in NDs, where oxidative stress and disrupted Ca 2+ homeostasis consequently lead to neuronal apoptosis. Reactive oxygen species (ROS) -sensitive TRP channels can be key risk factors as polymodal sensors, since progressive late onset with secondary pathological damage after initial toxic insult is one of the typical characteristics of NDs. Recent evidence indicates that the dysregulation of TRP channels is a missing link between disruption of Ca 2+ homeostasis and neuronal loss in NDs. In this review, we discuss the latest findings regarding TRP channels to provide insights into the research and quests for alternative therapeutic candidates for NDs. As the structures of TRP channels have recently been revealed by cryo-electron microscopy, it is necessary to develop new TRP channel antagonists and reevaluate existing drugs.

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“…It is tempting to speculate that the same mitoCa 2+ changes we observed in isolated neurons occur in vivo, and might contribute to the synergistic worsening of learning and memory in Drp1KO-hAPP mice. Indeed, mutations in APP and other proteins implicated in AD have been shown to disrupt cytosolic and ER calcium homeostasis (62)(63)(64), and Aß oligomers can increase mitoCa 2+ levels, perhaps due to increased uptake secondary to increased expression of the mitoCa 2+ uniporter (MCU) (65,66). Interestingly, patients with AD have decreased expression of the mitochondrial Na + /Ca 2+ exchanger (NCLX).…”

Section: Therapeutic Potential Of Decreasing Mitoca 2+ and Drp1 In Admentioning

confidence: 99%

Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity

Shields

Nguyen

et al. 2020

Preprint

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Alterations in mitochondrial fission may contribute to the pathophysiology of several neurodegenerative diseases, including Alzheimer's disease (AD). However, we understand very little about the normal functions of fission, or how fission disruption may interact with AD-associated proteins to modulate pathogenesis. Here we show that loss of the central mitochondrial fission protein dynamin-related 1 (Drp1) in CA1 and other forebrain neurons markedly worsens the learning and memory of mice expressing mutant human amyloid-precursor protein (hAPP) in neurons. In cultured neurons, Drp1KO and hAPP converge to produce mitochondrial Ca 2+ (mitoCa 2+ ) overload, despite decreasing mitochondriaassociated ER membranes (MAMs) and cytosolic Ca 2+ . This mitoCa 2+ overload occurs independently of ATP levels. These findings reveal a potential mechanism by which mitochondrial fission protects against hAPP-driven pathology.

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Amyloid β Oligomers Increase ER-Mitochondria Ca2+ Cross Talk in Young Hippocampal Neurons and Exacerbate Aging-Induced Intracellular Ca2+ Remodeling

Cited by 91 publications

References 75 publications

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

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

TRP Channels as Emerging Therapeutic Targets for Neurodegenerative Diseases

Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity

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