Calcium and Neurodegeneration

ArticleinAging Cell 6(3):337-50 · July 2007with24 Reads
DOI: 10.1111/j.1474-9726.2007.00275.x · Source: PubMed
When properly controlled, Ca2+ fluxes across the plasma membrane and between intracellular compartments play critical roles in fundamental functions of neurons, including the regulation of neurite outgrowth and synaptogenesis, synaptic transmission and plasticity, and cell survival. During aging, and particularly in neurodegenerative disorders, cellular Ca2+-regulating systems are compromised resulting in synaptic dysfunction, impaired plasticity and neuronal degeneration. Oxidative stress, perturbed energy metabolism and aggregation of disease-related proteins (amyloid beta-peptide, alpha-synuclein, huntingtin, etc.) adversely affect Ca2+ homeostasis by mechanisms that have been elucidated recently. Alterations of Ca2+-regulating proteins in the plasma membrane (ligand- and voltage-gated Ca2+ channels, ion-motive ATPases, and glucose and glutamate transporters), endoplasmic reticulum (presenilin-1, Herp, and ryanodine and inositol triphosphate receptors), and mitochondria (electron transport chain proteins, Bcl-2 family members, and uncoupling proteins) are implicated in age-related neuronal dysfunction and disease. The adverse effects of aging on neuronal Ca2+ regulation are subject to modification by genetic (mutations in presenilins, alpha-synuclein, huntingtin, or Cu/Zn-superoxide dismutase; apolipoprotein E isotype, etc.) and environmental (dietary energy intake, exercise, exposure to toxins, etc.) factors that may cause or affect the risk of neurodegenerative disease. A better understanding of the cellular and molecular mechanisms that promote or prevent disturbances in cellular Ca2+ homeostasis during aging may lead to novel approaches for therapeutic intervention in neurological disorders such as Alzheimer's and Parkinson's diseases and stroke.
    • The overall effect of the observed changes in gene expression is likely to be dysregulation of calcium homeostasis in senescent rotifers, leading to an increased intracellular calcium load that may negatively impact neuronal excitability [57][58][59]. In other model systems, loss of calcium homeostasis has been shown to be common to several age-related neurodegenerative diseases, including Alzheimers, Parkinson's, and ALS [54, 60, 61] . The dysregulation of signaling and of sensing pathways, including neuron recognition and chemotaxis, beginning as soon as the early-reproductive period should be investigated further.
    [Show abstract] [Hide abstract] ABSTRACT: Background Understanding gene expression changes over lifespan in diverse animal species will lead to insights to conserved processes in the biology of aging and allow development of interventions to improve health. Rotifers are small aquatic invertebrates that have been used in aging studies for nearly 100 years and are now re-emerging as a modern model system. To provide a baseline to evaluate genetic responses to interventions that change health throughout lifespan and a framework for new hypotheses about the molecular genetic mechanisms of aging, we examined the transcriptome of an asexual female lineage of the rotifer Brachionus manjavacas at five life stages: eggs, neonates, and early-, late-, and post-reproductive adults. ResultsThere are widespread shifts in gene expression over the lifespan of B. manjavacas; the largest change occurs between neonates and early reproductive adults and is characterized by down-regulation of developmental genes and up-regulation of genes involved in reproduction. The expression profile of post-reproductive adults was distinct from that of other life stages. While few genes were significantly differentially expressed in the late- to post-reproductive transition, gene set enrichment analysis revealed multiple down-regulated pathways in metabolism, maintenance and repair, and proteostasis, united by genes involved in mitochondrial function and oxidative phosphorylation. Conclusions This study provides the first examination of changes in gene expression over lifespan in rotifers. We detected differential expression of many genes with human orthologs that are absent in Drosophila and C. elegans, highlighting the potential of the rotifer model in aging studies. Our findings suggest that small but coordinated changes in expression of many genes in pathways that integrate diverse functions drive the aging process. The observation of simultaneous declines in expression of genes in multiple pathways may have consequences for health and longevity not detected by single- or multi-gene knockdown in otherwise healthy animals. Investigation of subtle but genome-wide change in these pathways during aging is an important area for future study.
    Full-text · Article · Dec 2017
    • To our knowledge, this study is the first to demonstrate that the neuroprotective effect of celastrol is associated with its attenuating Cd-induced Ca 2þ /CaMKII-dependent activation of Akt/mTOR pathway. Considering that disturbances in cellular Ca 2þ homeostasis have been highlighted in various neuropathological conditions, such as synaptic dysfunction, impaired plasticity, and neuronal degeneration, including Cd-induced neurotoxicity (Gibbons et al., 1993;Mattson, 2007;Toescu and Verkhratsky, 2007;Marambaud et al., 2009;Chen et al., 2011;Xu et al., 2011), weFig. 6.
    [Show abstract] [Hide abstract] ABSTRACT: Cadmium (Cd), an environmental and industrial pollutant, affects the nervous system and consequential neurodegenerative disorders. Recently we have shown that celastrol prevents Cd-induced neuronal cell death partially by suppressing Akt/mTOR pathway. However, the underlying mechanism remains to be elucidated. Here we show that celastrol attenuated Cd-elevated intracellular free calcium ([Ca2+]i) level and apoptosis in neuronal cells. Celastrol prevented Cd-induced neuronal apoptosis by inhibiting Akt-mediated mTOR pathway, as inhibition of Akt with Akt inhibitor X or ectopic expression of dominant negative Akt reinforced celastrol's prevention of Cd-induced phosphorylation of S6K1/4E-BP1 and cell apoptosis. Furthermore, chelating intracellular Ca2+ with BAPTA/AM or preventing [Ca2+]i elevation using EGTA potentiated celastrol's repression of Cd-induced [Ca2+]i elevation and consequential activation of Akt/mTOR pathway and cell apoptosis. Moreover, celastrol blocked Cd-elicited phosphorylation of CaMKII, and pretreatment with BAPTA/AM or EGTA enhanced celastrol's suppression of Cd-increased phosphorylation of CaMKII in neuronal cells, implying that celastrol hinders [Ca2+]i-mediated CaMKII phosphorylation. Inhibiting CaMKII with KN93 or silencing CaMKII attenuated Cd activation of Akt/mTOR pathway and cell apoptosis, and this was strengthened by celastrol. Taken together, these data demonstrate that celastrol attenuates Cd-induced neuronal apoptosis via inhibiting Ca2+-CaMKII-dependent Akt/mTOR pathway. Our findings underscore that celastrol may act as a neuroprotective agent for the prevention of Cd-induced neurodegenerative disorders. This article is protected by copyright. All rights reserved
    Full-text · Article · Feb 2017
    • The altered activities of these enzymes may contribute to abnormal neuronal circuit functioning in such neuropathological conditions (Ji et al., 2009). Impairment in Ca 2+ homeostasis is a common feature in Alzheimer's disease and other neurodegenerative disorders involving damage and death of neurons (Mattson, 2007; Bezprozvanny and Mattson, 2008; Thibault et al., 2012). Intracellular Ca 2+ are utilized by neurons in the control of various processes.
    Full-text · Article · Jul 2016
    • In addition, it has been proposed that Aβ causes Ca 2+ dyshomeostasis by different ways including increased Ca 2+ release from the intracellular sources (Chan et al., 2000; Tu et al., 2006) and/or increased Ca 2+ influx through the plasma membrane channels such as L-type voltage-gated Ca 2+ channels and NMDA receptors (Anekonda et al., 2011; Texido et al., 2011). Moreover, different forms of Aβ may impair neuronal function, and adversely affect synaptic functions in AD by increasing intracellular Ca 2+ (Bezprozvanny and Mattson, 2008; Haass and Selkoe, 2007; Mattson, 2007). Consistently, intracellular Ca 2+ dyshomeostasis has been shown in patients and in different experimental models of AD (Frandsen and Schousboe, 1991; Hardy and Selkoe, 2002; Thal et al., 2002; van Groen et al., 2003).
    [Show abstract] [Hide abstract] ABSTRACT: Entorhinal-hippocampal network is one of the earliest circuits which is affected by Alzheimer's disease (AD). There are numerous data providing the evidence of synaptic deficit in the dentate gyrus (DG) of AD animal model. However, there is little known about how entorhinal cortex (EC) amyloidophaty affects each excitatory and/or inhibitory transmission in the early stage of AD. On the other hand, it is believed that calcium dyshomeostasis has a critical role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on excitatory or inhibitory post synaptic currents (EPSC and IPSC, respectively) in the DG granule cells and then the possible neuroprotective action of L-type calcium channel blockers (CCBs), nimodipine and isradipine, were examined. The amyloid beta (Aβ) 1-42 was injected bilaterally into the EC of male rats and one week later, synaptic currents in the DG granule cells were assessed by whole cell patch clamp. EPSCs were evoked by stimulating the perforant pathway. Voltage clamp recording showed profound decrease of evoked EPSC amplitude and paired pulse facilitation in the DG granule cells of Aβ treated rats. Furthermore, AMPA/NMDA ratio was significantly decreased in the Aβ treated animals. On the other hand, amplitude of IPSC currents was significantly increased in the DG granule cells of these animals. These modifications of synaptic currents were partially reversed by daily intracerebroventricular administration of isradipine or nimodipine. In conclusion, our results suggest that Aβ in the EC triggers decreased excitatory transmission in the DG with substantial decrement in AMPA currents, leading to a prominent activity of inhibitory circuits and increased inhibition of granule cells which may contribute to the development of AD-related neurological deficits in AD and treatment by CCBs could preserve normal synaptic transmission against Aβ toxicity. This article is protected by copyright. All rights reserved.
    Article · May 2016
    • Additionally, the N-truncated Aβ 4−42 also abounds in AD brains and spawns stable Aβ 4−42 -os which are as neurotoxic as Aβ 1−42 -os and pE-Aβ 3−42 -os in vitro and in the mouse Tg4-42 transgenic line (Bouter et al., 2013). Moreover, interactions with cell membranes increase the aggregation rate of Aβ 42 -os and produce amyloid pores and Ca 2+ -permeable channels resulting in an intracellular Ca 2+ dyshomeostasis promoting the neurodegeneration (Mattson, 2007; Kawahara, 2010; Zhao et al., 2012; Berridge, 2014). However, being pathologically bound and activated by Aβ 42 -os, the calcium-sensing receptor (CaSR) expressed by all types of neural cells is also involved in AD development via mechanisms implicating much more than Ca 2+ influxes.
    [Show abstract] [Hide abstract] ABSTRACT: In aged subjects, late-onset Alzheimer’s disease (LOAD) starts in the lateral entorhinal allocortex where a failure of clearance mechanisms triggers an accumulation neurotoxic of amyloid-β42 oligomers (Aβ42-os). In neurons and astrocytes, Aβ42-os enhance the transcription of Aβ precursor protein (APP) and β-secretase/BACE1 genes. Thus, by acting together with γ-secretase, the surpluses of APP and BACE1 amplify the endogenous production of Aβ42-os which pile up, damage mitochondria, and are oversecreted. At the plasmalemma, exogenous Aβ42-os bind neurons' and astrocytes' calcium-sensing receptors (CaSRs) activating a set of intracellular signalling pathways which upkeep Aβ42-os intracellular accumulation and oversecretion by hindering Aβ42-os proteolysis. In addition, Aβ42-os accumulating in the extracellular milieu spread and reach mounting numbers of adjacent and remoter teams of neurons and astrocytes which in turn are recruited, again via Aβ42-osCaSR-governed mechanisms, to produce and release additional Aβ42-os amounts. This relentless self-sustaining mechanism drives AD progression towards upper cortical areas. Later on accumulating Aβ42-os elicit the advent of hyperphosphorylated (p)-Tau oligomers which acting together with Aβ42-os and other glial neurotoxins cooperatively destroy wider and wider cognition-related cortical areas. In parallel, Aβ42-osCaSR signals also elicit an excess production and secretion of nitric oxide and vascular endothelial growth factor-A from astrocytes, of Aβ42-os and myelin basic protein from oligodendrocytes, and of proinflammatory cytokines, nitric oxide and (likely) Aβ42-os from microglia. Activated astrocytes and microglia survive the toxic onslaught, whereas neurons and oligodendrocytes increasingly die. However, we have shown that highly selective allosteric CaSR antagonists (calcilytics), like NPS 2143 and NPS 89626, efficiently suppress all the neurotoxic effects Aβ42-osCaSR signalling drives in cultured cortical untransformed human neurons and astrocytes. In fact, calcilytics increase Aβ42 proteolysis and discontinue the oversecretion of Aβ42-os, nitric oxide, and vascular endothelial growth factor-A from both astrocytes and neurons. Seemingly, calcilytics would also benefit the other types of glial cells and cerebrovascular cells otherwise damaged by the effects of Aβ42-osCaSR signalling. Thus, given at amnestic minor cognitive impairment (aMCI) or initial symptomatic stages, calcilytics could prevent or terminate the propagation of LOAD neuropathology and preserve human neurons' viability and hence patients’ cognitive abilities.
    Full-text · Article · Apr 2016
    • In this respect it is noteworthy that recent research in a group of Parkinson's patients in an agricultural area of the Netherlands identified exposure to dinitrophenolic herbicides as a common denominator (unpublished results). Though mechanisms underlying pesticide-induced (dopaminergic ) neurodegeneration are largely unknown, disturbance of mitochondrial phosphorylation, changes in the intracellular calcium concentration ([Ca 2+ ] i ) and in particular Ca 2+ -related endoplasmic reticulum (ER) stress are recognized as inducers of tissue damage in dopaminergic brain areas (Mattson, 2007; Bartels and Leenders, 2009; Bezprozvanny, 2009; Heusinkveld et al., 2014). Subsequent protein misfolding and aggregation contributes to the development of cytoplasmic inclusions, such as a-synuclein-containing Lewy bodies that are a common pathophysiological hallmark of PD (Marques and Outeiro 2012; Witt, 2013).
    [Show abstract] [Hide abstract] ABSTRACT: Dinitrophenolic compounds are powerful toxicants with a long history of use in agriculture and industry. While (high) human exposure levels are not uncommon, in particular for agricultural workers during the spraying season, the neurotoxic mechanism(s) that underlie the human health effects are largely unknown. We therefore investigated the in vitro effects of two dinitrophenolic herbicides (DNOC and dinoseb) on a battery of neurotoxicity endpoints in (dopaminergic) rat PC12 cells. Cell viability, mitochondrial activity, oxidative stress and caspase activation were assessed using fluorescence-based bioassays (CFDA, alamar Blue, H2DCFDA and Ac-DEVD-AMC, respectively), whereas changes in intracellular [Ca2+]i were assessed using single-cell fluorescence microscopy with Fura-2AM. The combined results demonstrate that exposure to both DNOC and dinoseb is linked to calcium release from the endoplasmic reticulum and activation of caspase-mediated apoptotic pathways. In subsequent experiments, immunofluorescent labelling with specific antibodies was used to determine changes in intracellular α-synuclein levels, demonstrating that both DNOC and dinoseb increase levels of intracellular α-synuclein. The combined results indicate that in vitro exposure to DNOC and dinoseb activates pathways that are not only involved in acute neurotoxicity but also in long-term effects as seen in neurodegeneration.
    Full-text · Article · Apr 2016
Show more