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FAD Mutations in Amyloid Precursor Protein Do Not Directly Perturb Intracellular Calcium Homeostasis  [PDF]
Emily Stieren,Walter P. Werchan,Amina El Ayadi,Fuzhen Li,Darren Boehning
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011992
Abstract: Disturbances in intracellular calcium homeostasis are likely prominent and causative factors leading to neuronal cell death in Alzheimer's disease (AD). Familial AD (FAD) is early-onset and exhibits autosomal dominant inheritance. FAD-linked mutations have been found in the genes encoding the presenilins and amyloid precursor protein (APP). Several studies have shown that mutated presenilin proteins can directly affect calcium release from intracellular stores independently of Aβ production. Although less well established, there is also evidence that APP may directly modulate intracellular calcium homeostasis. Here, we directly examined whether overexpression of FAD-linked APP mutants alters intracellular calcium dynamics. In contrast to previous studies, we found that overexpression of mutant APP has no effects on basal cytosolic calcium, ER calcium store size or agonist-induced calcium release and subsequent entry. Thus, we conclude that mutated APP associated with FAD has no direct effect on intracellular calcium homeostasis independently of Aβ production.
The acute neurotoxicity of mefloquine may be mediated through a disruption of calcium homeostasis and ER function in vitro
Geoffrey S Dow, Thomas H Hudson, Maryanne Vahey, Michael L Koenig
Malaria Journal , 2003, DOI: 10.1186/1475-2875-2-14
Abstract: Laser scanning confocal microscopy was employed to monitor real-time changes in basal intracellular calcium concentrations in embryonic rat neurons in response to mefloquine and thapsigargin (a known inhibitor of the ER calcium pump) in the presence and absence of external calcium. Changes in the transcriptional regulation of known ER stress response genes in neurons by mefloquine were investigated using Affymetrix arrays. The MTT assay was employed to measure the acute neurotoxicity of mefloquine and its antagonisation by thapsigargin.At physiologically relevant concentrations mefloquine was found to mobilize neuronal ER calcium stores and antagonize the pharmacological action of thapsigargin, a specific inhibitor of the ER calcium pump. Mefloquine also induced a sustained influx of extra-neuronal calcium via an unknown mechanism. The transcription of key ER proteins including GADD153, PERK, GRP78, PDI, GRP94 and calreticulin were up-regulated by mefloquine, suggesting that the drug induced an ER stress response. These effects appear to be related, in terms of dose effect and kinetics of action, to the acute neurotoxicity of the drug in vitro.Mefloquine was found to disrupt neuronal calcium homeostasis and induce an ER stress response at physiologically relevant concentrations, effects that may contribute, at least in part, to the neurotoxicity of the drug in vitro.Mefloquine is a prophylactic antimalarial drug that is also used for malaria chemotherapy. Adverse central nervous system (CNS) events have been associated with its use [1,2]. Severe CNS events requiring hospitalization occur in 1:10,000 and 1:200–1200 patients taking mefloquine for chemoprophylaxis or treatment, respectively [1,2]. Milder CNS events (e.g. dizziness, headache and insomnia) are a more frequent occurrence, being experienced by up to 25% of patients receiving chemoprophylactic doses and 90% of those receiving therapeutic doses [1,2]. Higher blood levels of mefloquine are reached under thera
Disruption of Calcium Homeostasis in Cardiomyocytes Underlies Cardiac Structural and Functional Changes in Severe Sepsis  [PDF]
Mara R. N. Celes, Lygia M. Malvestio, Sylvia O. Suadicani, Cibele M. Prado, Maria J. Figueiredo, Erica C. Campos, Ana C. S. Freitas, David C. Spray, Herbert B. Tanowitz, Jo?o S. da Silva, Marcos A. Rossi
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0068809
Abstract: Sepsis, a major cause of morbidity/mortality in intensive care units worldwide, is commonly associated with cardiac dysfunction, which worsens the prognosis dramatically for patients. Although in recent years the concept of septic cardiomyopathy has evolved, the importance of myocardial structural alterations in sepsis has not been fully explored. This study offers novel and mechanistic data to clarify subcellular events that occur in the pathogenesis of septic cardiomyopathy and myocardial dysfunction in severe sepsis. Cultured neonatal mice cardiomyocytes subjected to serum obtained from mice with severe sepsis presented striking increment of [Ca2+]i and calpain-1 levels associated with decreased expression of dystrophin and disruption and derangement of F-actin filaments and cytoplasmic bleb formation. Severe sepsis induced in mice led to an increased expression of calpain-1 in cardiomyocytes. Moreover, decreased myocardial amounts of dystrophin, sarcomeric actin, and myosin heavy chain were observed in septic hearts associated with depressed cardiac contractile dysfunction and a very low survival rate. Actin and myosin from the sarcomere are first disassembled by calpain and then ubiquitinated and degraded by proteasome or sequestered inside specialized vacuoles called autophagosomes, delivered to the lysosome for degradation forming autophagolysosomes. Verapamil and dantrolene prevented the increase of calpain-1 levels and preserved dystrophin, actin, and myosin loss/reduction as well cardiac contractile dysfunction associated with strikingly improved survival rate. These abnormal parameters emerge as therapeutic targets, which modulation may provide beneficial effects on future vascular outcomes and mortality in sepsis. Further studies are needed to shed light on this mechanism, mainly regarding specific calpain inhibitors.
Neurosteroids block the increase in intracellular calcium level induced by Alzheimer’s β-amyloid protein in long-term cultured rat hippocampal neurons
Midori Kato-Negishi,Masahiro Kawahara
Neuropsychiatric Disease and Treatment , 2008,
Abstract: Midori Kato-Negishi1, Masahiro Kawahara21Department of Developmental Morphology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu-shi, Tokyo 183- 8526, Japan; 2Department of Analytical Chemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino-cho, Nobeoka-shi, Miyazaki 882-8508, JapanAbstract: The neurotoxicity of β-amyloid protein (AβP) is implicated in the etiology of Alzheimer’s disease. We previously have demonstrated that AβP forms Ca2+-permeable pores on neuronal membranes, causes a marked increase in intracellular calcium level, and leads to neuronal death. Here, we investigated in detail the features of AβP-induced changes in intracellular Ca2+ level in primary cultured rat hippocampal neurons using a multisite Ca2+- imaging system with fura-2 as a fluorescent probe. Only a small fraction of short-term cultured hippocampal neurons (ca 1 week in vitro) exhibited changes in intracellular Ca2+ level after AβP exposure. However, AβP caused an acute increase in intracellular Ca2+ level in long-term cultured neurons (ca 1 month in vitro). The responses to AβP were highly heterogeneous, and immunohistochemical analysis using an antibody to AβP revealed that AβP is deposited on some but not all neurons. Considering that the disruption of Ca2+ homeostasis is the primary event in AβP neurotoxicity, substances that protect neurons from an AβP-induced intracellular Ca2+ level increase may be candidates as therapeutic drugs for Alzheimer’s disease. In line with the search for such protective substances, we found that the preadministration of neurosteroids including dehydroepiandrosterone, dehydroepiandrosterone sulfate, and pregnenolone significantly inhibits the increase in intracellular calcium level induced by AβP. Our results suggest the possible significance of neurosteroids, whose levels are reduced in the elderly, in preventing AβP neurotoxicity.Keywords: neurotoxicity, pore, calcium homeostasis, channel, aging
Control of calcium homeostasis in Schistosoma mansoni
No?l, F;Cunha, VMN;Silva, CLM;Mendon?a-Silva, DL;
Memórias do Instituto Oswaldo Cruz , 2001, DOI: 10.1590/S0074-02762001000900012
Abstract: calcium signalling is fundamental for muscular contractility of schistosoma mansoni. we have previously described the presence of transport atpases (na+,k+-atpase and (ca2+-mg2+)-atpase) and calcium channels (ryanodine receptors - ryr) involved in control of calcium homeostasis in this worm. here we briefly review the main technics (atpase activity, binding with specific radioligands, fluxes of 45ca2+ and whole worm contractions) and results obtained in order to compare the distribution patterns of these proteins: thapsigargin-sensitive (ca2+-mg2+)-atpase activity and ryr co-purified in p1 and p4 fractions mainly, which is compatible with a sarcoplasmic reticulum localization, while basal atpase (along with na+,k+-atpase) and thapsigargin-resistant (ca2+-mg2+)-atpase have a distinct distribution, indicative of their plasma membrane localization. finally we attempt to integrate these contributions with data from other groups in order to propose the first synoptic model for control of calcium homeostasis in s. mansoni.
Control of calcium homeostasis in Schistosoma mansoni  [cached]
No?l F,Cunha VMN,Silva CLM,Mendon?a-Silva DL
Memórias do Instituto Oswaldo Cruz , 2001,
Abstract: Calcium signalling is fundamental for muscular contractility of Schistosoma mansoni. We have previously described the presence of transport ATPases (Na+,K+-ATPase and (Ca2+-Mg2+)-ATPase) and calcium channels (ryanodine receptors - RyR) involved in control of calcium homeostasis in this worm. Here we briefly review the main technics (ATPase activity, binding with specific radioligands, fluxes of 45Ca2+ and whole worm contractions) and results obtained in order to compare the distribution patterns of these proteins: thapsigargin-sensitive (Ca2+-Mg2+)-ATPase activity and RyR co-purified in P1 and P4 fractions mainly, which is compatible with a sarcoplasmic reticulum localization, while basal ATPase (along with Na+,K+-ATPase) and thapsigargin-resistant (Ca2+-Mg2+)-ATPase have a distinct distribution, indicative of their plasma membrane localization. Finally we attempt to integrate these contributions with data from other groups in order to propose the first synoptic model for control of calcium homeostasis in S. mansoni.
Circadian Disruption Leads to Loss of Homeostasis and Disease  [PDF]
Carolina Escobar,Roberto Salgado-Delgado,Eduardo Gonzalez-Guerra,Araceli Tapia Osorio,Manuel Angeles-Castellanos,Ruud M. Buijs
Sleep Disorders , 2011, DOI: 10.1155/2011/964510
Abstract: The relevance of a synchronized temporal order for adaptation and homeostasis is discussed in this review. We present evidence suggesting that an altered temporal order between the biological clock and external temporal signals leads to disease. Evidence mainly based on a rodent model of “night work” using forced activity during the sleep phase suggests that altered activity and feeding schedules, out of phase from the light/dark cycle, may be the main cause for the loss of circadian synchrony and disease. It is proposed that by avoiding food intake during sleep hours the circadian misalignment and adverse consequences can be prevented. This review does not attempt to present a thorough revision of the literature, but instead it aims to highlight the association between circadian disruption and disease with special emphasis on the contribution of feeding schedules in circadian synchrony. 1. The Relevance of Circadian Rhythms for Homeostasis Our physiology is organized around the daily cycle of activity and sleep [1]. In the active phase, when energy expenditure is high and food and water are consumed, organs need to be prepared for the intake, processing, and uptake of nutrients. During sleep, energy expenditure and digestive processes decrease and cellular repair takes place [1, 2]. The autonomic nervous system and hormones, especially melatonin and corticosterone, are used to transmit signals from hypothalamic and brain stem nuclei to the body in order to prepare it for the daily changes in activity, food intake, and rest. Hypothalamic structures receive information from the suprachiasmatic nucleus (SCN), the biological clock [1, 2]; this nucleus transmits 24?h time information synchronized by the light dark (LD) cycle. It is known that neurons of the SCN, even in vitro, maintain a 24?h rhythm of electrical activity and neurotransmitter, release [3]. Via the secretion of its neurotransmitters, the SCN transmits rhythmicity to hypothalamic structures, to the brain, and to the rest of the body. An example is the secretion of corticotrophin releasing hormone and thus the secretion of ACTH, which is modulated by the SCN via vasopressin projections to the dorsomedial hypothalamus (DMH) and subsequently to the paraventricular nucleus (PVN) [4]. Simultaneously, the SCN modifies the sensitivity of the adrenal gland for ACTH via the preautonomic sympathetic neurons of the PVN, thus creating the most efficient way to transmit its time message to the body [5]. Light influences directly the neuronal activity of the SCN and thus inhibits melatonin secretion from
Selenomethionine Incorporation into Amyloid Sequences Regulates Fibrillogenesis and Toxicity  [PDF]
Javier Martínez, Silvia Lisa, Rosa Sánchez, Wioleta Kowalczyk, Esther Zurita, Meritxell Teixidó, Ernest Giralt, David Andreu, Jesús Avila, María Gasset
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027999
Abstract: Background The capacity of a polypeptide chain to engage in an amyloid formation process and cause a conformational disease is contained in its sequence. Some of the sequences undergoing fibrillation contain critical methionine (Met) residues which in vivo can be synthetically substituted by selenomethionine (SeM) and alter their properties. Methodology/Principal Findings Using peptide synthesis, biophysical techniques and cell viability determinations we have studied the effect of the substitution of methionine (Met) by selenomethionine (SeM) on the fibrillogenesis and toxic properties of Aβ40 and HuPrP(106–140). We have found that the effects display site-specificity and vary from inhibition of fibrillation and decreased toxicity ([SeM35]Aβ40, [SeM129]HuPrP(106–140) and [SeM134]HuPrP(106–140)), retarded assembly, modulation of polymer shape and retention of toxicity ([SeM112]HuPrP(106–140) to absence of effects ([SeM109]HuPrP(106–140)). Conclusions/Significance This work provides direct evidence that the substitution of Met by SeM in proamyloid sequences has a major impact on their self-assembly and toxic properties, suggesting that the SeM pool can play a major role in dictating the allowance and efficiency of a polypeptide chain to undergo toxic polymerization.
Modes of Neuronal Calcium Entry and Homeostasis following Cerebral Ischemia
J. L. Cross,B. P. Meloni,A. J. Bakker,S. Lee,N. W. Knuckey
Stroke Research and Treatment , 2010, DOI: 10.4061/2010/316862
Abstract: One of the major instigators leading to neuronal cell death and brain damage following cerebral ischemia is calcium dysregulation. The neuron's inability to maintain calcium homeostasis is believed to be a result of increased calcium influx and impaired calcium extrusion across the plasma membrane. The need to better understand the cellular and biochemical mechanisms of calcium dysregulation contributing to neuronal loss following stroke/cerebral ischemia is essential for the development of new treatments in order to reduce ischemic brain injury. The aim of this paper is to provide a concise overview of the various calcium influx pathways in response to ischemia and how neuronal cells attempts to overcome this calcium overload.
Calcium Ions Promote Formation of Amyloid β-Peptide (1–40) Oligomers Causally Implicated in Neuronal Toxicity of Alzheimer's Disease  [PDF]
Anna Itkin,Vincent Dupres,Yves F. Dufrêne,Burkhard Bechinger,Jean-Marie Ruysschaert,Vincent Raussens
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018250
Abstract: Amyloid β-peptide (Aβ) is directly linked to Alzheimer's disease (AD). In its monomeric form, Aβ aggregates to produce fibrils and a range of oligomers, the latter being the most neurotoxic. Dysregulation of Ca2+ homeostasis in aging brains and in neurodegenerative disorders plays a crucial role in numerous processes and contributes to cell dysfunction and death. Here we postulated that calcium may enable or accelerate the aggregation of Aβ. We compared the aggregation pattern of Aβ(1–40) and that of Aβ(1–40)E22G, an amyloid peptide carrying the Arctic mutation that causes early onset of the disease. We found that in the presence of Ca2+, Aβ(1–40) preferentially formed oligomers similar to those formed by Aβ(1–40)E22G with or without added Ca2+, whereas in the absence of added Ca2+ the Aβ(1–40) aggregated to form fibrils. Morphological similarities of the oligomers were confirmed by contact mode atomic force microscopy imaging. The distribution of oligomeric and fibrillar species in different samples was detected by gel electrophoresis and Western blot analysis, the results of which were further supported by thioflavin T fluorescence experiments. In the samples without Ca2+, Fourier transform infrared spectroscopy revealed conversion of oligomers from an anti-parallel β-sheet to the parallel β-sheet conformation characteristic of fibrils. Overall, these results led us to conclude that calcium ions stimulate the formation of oligomers of Aβ(1–40), that have been implicated in the pathogenesis of AD.
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