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Melitta Schachner - One of the best experts on this subject based on the ideXlab platform.
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Neural Cell Adhesion Molecules of the Immunoglobulin Superfamily Regulate Synapse Formation, Maintenance, and Function
Trends in neurosciences, 2017Co-Authors: Vladimir Sytnyk, Iryna Leshchyns'ka, Melitta SchachnerAbstract:Immunoglobulin superfamily adhesion molecules are among the most abundant proteins in vertebrate and invertebrate nervous systems. Prominent family members are the Neural Cell adhesion molecules NCAM and L1, which were the first to be shown to be essential not only in development but also in synaptic function and as key regulators of synapse formation, synaptic activity, plasticity, and synaptic vesicle recycling at distinct developmental and activity stages. In addition to interacting with each other, adhesion molecules interact with ion channels and cytokine and neurotransmitter receptors. Mutations in their genes are linked to neurological disorders associated with abnormal development and synaptic functioning. This review presents an overview of recent studies on these molecules and their crucial impact on neurological disorders.
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Interactions of the Neural Cell Adhesion Molecule and the Myelin-associated Glycoprotein with Collagen Type I: Involvement in Fibrillogenesis
2013Co-Authors: Rainer Probstmeier, Thomas Fahrig, Eberhard Spiess, Melitta SchachnerAbstract:Abstract. To gain insights into the functional role of the molecular association between Neural adhesion molecules and extraCellular matrix constituents, soluble forms of the myelin-associated glycoprotein (MAG) and the Neural Cell adhesion molecule (N-CAM), representing most of the extraCellular domains of the molecules, were investigated in their ability to modify fibrillogenesis of collagen type 1. MAG and N-CAM retarded the rate of fibril formation, as measured by changes in turbidity, and increased the diameter of the fibrils formed, but did not change the banding pattern when compared to collagen type I in the absence of adhesion molecules. Scatchard plot analysis of the binding of MAG and N-CAM to the fibril-forming collagen types 1, II, III, and V suggest one binding site fo
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polysialylated Neural Cell adhesion molecule promotes remodeling and formation of hippocampal synapses
The Journal of Neuroscience, 2004Co-Authors: Alexander Dityatev, Vladimir Sytnyk, Galina Dityateva, Markus Delling, Nicolas Toni, Irina Nikonenko, Dominique Muller, Melitta SchachnerAbstract:Expression of the Neural Cell adhesion molecule (NCAM) has been shown to promote long-term potentiation (LTP) and stabilization of synapses during early synaptogenesis. Here, we searched for the mechanisms of synaptogenic activity of NCAM, focusing on the role of polysialic acid (PSA), an unusual carbohydrate preferentially associated with NCAM. We show that enzymatic removal of PSA with endoneuraminidase-N (endo-N) abolished preferential formation of synapses on NCAM-expressing Cells in heterogenotypic cocultures of wild-type and NCAM-deficient hippocampal neurons. Transfection of NCAM-deficient neurons with either of three major NCAM isoforms (different in intraCellular domains but identical in extraCellular domains and carrying PSA) stimulated preferential synapse formation on NCAM isoform-expressing neurons. Enzymatic removal of heparan sulfates from cultured neurons and a mutation in the heparin-binding domain of NCAM diminished synaptogenic activity of neuronally expressed PSA-NCAM, suggesting that interaction of NCAM with heparan sulfate proteoglycans mediates this activity. PSA-NCAM-driven synaptogenesis was also blocked by antagonists to fibroblast growth factor receptor and NMDA subtype of glutamate receptors but not by blockers of non-NMDA glutamate receptors and voltage-dependent Na+ channels. Enzymatic removal of PSA and heparan sulfates also blocked the increase in the number of perforated spine synapses associated with NMDA receptor-dependent LTP in the CA1 region of organotypic hippocampal cultures. Thus, neuronal PSA-NCAM in complex with heparan sulfate proteoglycans promotes synaptogenesis and activity-dependent remodeling of synapses.
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Neural Cell adhesion molecule l1 is required for fasciculation and routing of thalamocortical fibres and corticothalamic fibres
Neuroscience Research, 2004Co-Authors: Melitta Schachner, Kyoji Ohyama, Kyoko Tantakeuchi, Michael Kutsche, Keiichi Uyemura, Koki KawamuraAbstract:To examine the role of Neural Cell adhesion molecule L1 in thalamocortical projections, we analysed L1 deficient (L1-/y) mice. Immunohistochemistry of pleiotrophin/HB-GAM, a marker for thalamocortical axons and axonal tracing experiments showed that thalamocortical axons were abnormally and highly fasciculated when they pass through the developing internal capsule. Within the cortex, however, their course was more diffuse. The corticofugal fibres immunoreactive for TAG-1 were also more strongly fasciculated and their number was decreased in L1-/y mice. Furthermore, no TAG-1-positive corticofugal axons reached the dorsal thalamus. These data suggest that L1 plays an important role in the fasciculation and routing of axons connecting between the thalamus and the cortex.
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increased immunogold labelling of Neural Cell adhesion molecule isoforms in synaptic active zones of the chick striatum 5 6 hours after one trial passive avoidance training
Neuroscience, 1997Co-Authors: G G Skibo, Heather A Davies, Dmitri A Rusakov, Michael G Stewart, Melitta SchachnerAbstract:Abstract An area of the chick striatum, the lobus parolfactorius plays an important role in one-trial passive avoidance learning tasks. 16 , 19 , 20 In the present study we report evidence that 5–6 h post-training, a significantly higher proportion of synaptic active zones in this area contain labelled epitopes of the Neural Cell adhesion molecule, with the greatest occurrence of labels at the edges of active zone profiles (in both control and trained groups). This suggests that there is a period after training when expression of the Neural Cell adhesion molecule in synaptic membranes almost doubles, and that events at active zone edges may play a specific role in mechanisms of synaptic adhesion. Cellular mechanisms of long-term memory formation are believed to include alterations in Neural circuitry at the synaptic level. The involvement of the Neural Cell adhesion molecule (NCAM) in functional synaptic modifications has been demonstrated using a number of physiological models. 6 , 9 , 13 Performance of rats in the Morris water maze, a spatial learning paradigm which requires the hippocampus, is impaired by either intraventricular injection of NCAM antibodies, [1] or injection into the hippocampus of an enzyme which increases homophilic adhesion of the molecule, due to the removal of polysialic acid residuals from extraCellular NCAM domains. [3] In addition, intraventricular injections of anti-NCAM antibodies 6–8 h post-training were shown to impair memory for a one-trial passive avoidance task in the rat. [7] An avoidance training model in the one-day-old chick indicates a similar time window, 5–6 h post-training during which memory for the task can be impaired by intraventricular injection of NCAM antibodies. 14 , 17 In the hyperstriatum ventrale, a chick forebrain area involved in the passive avoidance task, subtle changes in the distribution pattern, but not density of NCAM molecules in synaptic membranes were revealed 5–6 h post-training. [15] However, on the basis of studies of synaptic morphometry, a region of striatum, the lobus parolfactorius (LPO), appears to play a more important role in longer term memory storage for the task. 14 , 16 , 20
Elisabeth Bock - One of the best experts on this subject based on the ideXlab platform.
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the fibroblast growth factor receptor fgfr agonist fgf1 and the Neural Cell adhesion molecule derived peptide fgl activate fgfr substrate 2α differently
Journal of Neuroscience Research, 2010Co-Authors: Yongshuo Chen, Vladimir Berezin, Elisabeth BockAbstract:Activation of fibroblast growth factor (FGF) receptors (FGFRs) both by FGFs and by the Neural Cell adhesion molecule (NCAM) is crucial in the development and function of the nervous system. We found that FGFR substrate 2alpha (FRS2alpha), Src homologous and collagen A (ShcA), and phospholipase-Cgamma (PLCgamma) were all required for neurite outgrowth from cerebellar granule neurons (CGNs) induced by FGF1 and FGL (an NCAM-derived peptide agonist of FGFR1). Like FGF1, FGL induced tyrosine phosphorylation of FGFR1, FRS2alpha, ShcA, and PLCgamma in a time- and dose-dependent manner. However, the activation of FRS2alpha by FGL was significantly lower than the activation by FGF1, indicating a differential signaling profile induced by NCAM compared with the cognate growth factor.
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signalling pathways underlying Neural Cell adhesion molecule mediated survival of dopaminergic neurons
European Journal of Neuroscience, 2007Co-Authors: Dorte Kornerup Ditlevsen, Vladimir Berezin, Elisabeth BockAbstract:Stimulation of the Neural Cell adhesion molecule (NCAM) by homophilic interactions is known to lead to neurite outgrowth as well as to neuronal survival. Whereas a complex network of signalling molecules is known to be of importance to NCAM-mediated neurite extension, only limited information is available regarding signalling underlying NCAM-mediated neuroprotection. Here, we present data suggesting a difference in the signalling events required for survival of rat dopaminergic neurons as compared with neurite outgrowth from the same Cell type. Whereas Fyn, fibroblast growth factor receptor, mitogen-activated protein and ERK kinase, protein kinase A and protein kinase C are required for both responses to NCAM-induced signalling, phospholipase C and Ca(2+)-calmodulin-dependent kinase II are only necessary for the neurite outgrowth response, but dispensable for neuroprotection.
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cyclic guanosine monophosphate signalling pathway plays a role in Neural Cell adhesion molecule mediated neurite outgrowth and survival
Journal of Neuroscience Research, 2007Co-Authors: Dorte Kornerup Ditlevsen, Vladimir Berezin, Lene B Kohler, Elisabeth BockAbstract:The Neural Cell adhesion molecule (NCAM) plays a crucial role in neuronal development, regeneration, and synaptic plasticity associated with learning and memory consolidation. Homophilic binding of NCAM leads to neurite extension and neuroprotection in various types of primary neurons through activation of a complex network of signalling cascades, including fibroblast growth factor receptor, Src-family kinases, the mitogen-activated protein kinase pathway, protein kinase C, phosphatidylinositol-3 kinase, and an increase in intraCellular Ca(2+). Here we present data indicating an involvement of cyclic GMP in NCAM-mediated neurite outgrowth in both hippocampal and dopaminergic neurons and in NCAM-mediated neuroprotection of dopaminergic neurons. In addition, evidence is presented suggesting that NCAM mediates activation of cGMP via synthesis of nitric oxide (NO) by NO synthase (NOS) and activation of soluble guanylyl cyclase by NO, leading to an increased synthesis of cGMP and activation by cGMP of protein kinase G.
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cyclic guanosine monophosphate signalling pathway plays a role in Neural Cell adhesion molecule mediated neurite outgrowth and survival
Journal of Neuroscience Research, 2007Co-Authors: Dorte Kornerup Ditlevsen, Vladimir Berezin, Lene B Kohler, Elisabeth BockAbstract:The Neural Cell adhesion molecule (NCAM) plays a crucial role in neuronal development, regeneration, and synaptic plasticity associated with learning and memory consolidation. Homophilic binding of NCAM leads to neurite extension and neuroprotection in various types of primary neurons through activation of a complex network of signalling cascades, including fibroblast growth factor receptor, Src-family kinases, the mitogen-activated protein kinase pathway, protein kinase C, phosphatidylinositol-3 kinase, and an increase in intraCellular Ca2+. Here we present data indicating an involvement of cyclic GMP in NCAM-mediated neurite outgrowth in both hippocampal and dopaminergic neurons and in NCAM-mediated neuroprotection of dopaminergic neurons. In addition, evidence is presented suggesting that NCAM mediates activation of cGMP via synthesis of nitric oxide (NO) by NO synthase (NOS) and activation of soluble guanylyl cyclase by NO, leading to an increased synthesis of cGMP and activation by cGMP of protein kinase G. © 2007 Wiley-Liss, Inc.
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a synthetic Neural Cell adhesion molecule mimetic peptide promotes synaptogenesis enhances presynaptic function and facilitates memory consolidation
The Journal of Neuroscience, 2004Co-Authors: Karine Cambon, Vladimir Berezin, Elisabeth Bock, Cesar Venero, Stine Maria Hansen, Isabel A Herrero, Galina Skibo, Carmen SandiAbstract:The Neural Cell adhesion molecule (NCAM) plays a critical role in development and plasticity of the nervous system and is involved in the mechanisms of learning and memory. Here, we show that intracerebroventricular administration of the FG loop (FGL), a synthetic 15 amino acid peptide corresponding to the binding site of NCAM for the fibroblast growth factor receptor 1 (FGFR1), immediately after training rats in fear conditioning or water maze learning, induced a long-lasting improvement of memory. In primary cultures of hippocampal neurons, FGL enhanced the presynaptic function through activation of FGFR1 and promoted synapse formation. These results provide the first evidence for a memory-facilitating effect resulting from a treatment that mimics NCAM function. They suggest that increased efficacy of synaptic transmission and formation of new synapses probably mediate the cognition-enhancing properties displayed by the peptide.
Se Hoon Choi - One of the best experts on this subject based on the ideXlab platform.
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a 3d human Neural Cell culture system for modeling alzheimer s disease
Nature Protocols, 2015Co-Authors: Young Hye Kim, Se Hoon Choi, Carla Davanzo, Matthias Hebisch, Christopher Sliwinski, Enjana Bylykbashi, Kevin J Washicosky, Justin B Klee, Oliver Brustle, Rudolph E TanziAbstract:Stem Cell technologies have facilitated the development of human Cellular disease models that can be used to study pathogenesis and test therapeutic candidates. These models hold promise for complex neurological diseases such as Alzheimer's disease (AD), because existing animal models have been unable to fully recapitulate all aspects of pathology. We recently reported the characterization of a novel 3D culture system that exhibits key events in AD pathogenesis, including extraCellular aggregation of amyloid-β (Aβ) and accumulation of hyperphosphorylated tau. Here we provide instructions for the generation and analysis of 3D human Neural Cell cultures, including the production of genetically modified human Neural progenitor Cells (hNPCs) with familial AD mutations, the differentiation of the hNPCs in a 3D matrix and the analysis of AD pathogenesis. The 3D culture generation takes 1-2 d. The aggregation of Aβ is observed after 6 weeks of differentiation, followed by robust tau pathology after 10-14 weeks.
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recapitulating amyloid β and tau pathology in human Neural Cell culture models clinical implications
US neurology, 2015Co-Authors: Se Hoon Choi, Young Hye Kim, Carla Davanzo, Jenna Aronson, Rudolph E Tanzi, Doo Yeon KimAbstract:The "amyloid β hypothesis" of Alzheimer's disease (AD) has been the reigning hypothesis explaining pathogenic mechanisms of AD over the last two decades. However, this hypothesis has not been fully validated in animal models, and several major unresolved issues remain. We recently developed a human Neural Cell culture model of AD based on a three-dimensional (3D) Cell culture system. This unique, Cellular model recapitulates key events of the AD pathogenic cascade, including β-amyloid plaques and neurofibrillary tangles. Our 3D human Neural Cell culture model system provides a premise for a new generation of Cellular AD models that can serve as a novel platform for studying pathogenic mechanisms and for high-throughput drug screening in a human brain-like environment.
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a three dimensional human Neural Cell culture model of alzheimer s disease
Nature, 2014Co-Authors: Se Hoon Choi, Young Hye Kim, Carla Davanzo, Matthias Hebisch, Christopher Sliwinski, Seungkyu Lee, Hechao Chen, Basavaraj Hooli, Caroline Asselin, Julien MuffatAbstract:Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. However, to date, no single disease model has serially linked these two pathological events using human neuronal Cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extraCellular deposition of amyloid-β, including amyloid-β plaques, in a human Neural stem-Cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal Cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human Neural Cell culture system. Our unique strategy for recapitulating Alzheimer's disease pathology in a 3D Neural Cell culture model should also serve to facilitate the development of more precise human Neural Cell models of other neurodegenerative disorders.
Young Hye Kim - One of the best experts on this subject based on the ideXlab platform.
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a 3d human Neural Cell culture system for modeling alzheimer s disease
Nature Protocols, 2015Co-Authors: Young Hye Kim, Se Hoon Choi, Carla Davanzo, Matthias Hebisch, Christopher Sliwinski, Enjana Bylykbashi, Kevin J Washicosky, Justin B Klee, Oliver Brustle, Rudolph E TanziAbstract:Stem Cell technologies have facilitated the development of human Cellular disease models that can be used to study pathogenesis and test therapeutic candidates. These models hold promise for complex neurological diseases such as Alzheimer's disease (AD), because existing animal models have been unable to fully recapitulate all aspects of pathology. We recently reported the characterization of a novel 3D culture system that exhibits key events in AD pathogenesis, including extraCellular aggregation of amyloid-β (Aβ) and accumulation of hyperphosphorylated tau. Here we provide instructions for the generation and analysis of 3D human Neural Cell cultures, including the production of genetically modified human Neural progenitor Cells (hNPCs) with familial AD mutations, the differentiation of the hNPCs in a 3D matrix and the analysis of AD pathogenesis. The 3D culture generation takes 1-2 d. The aggregation of Aβ is observed after 6 weeks of differentiation, followed by robust tau pathology after 10-14 weeks.
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recapitulating amyloid β and tau pathology in human Neural Cell culture models clinical implications
US neurology, 2015Co-Authors: Se Hoon Choi, Young Hye Kim, Carla Davanzo, Jenna Aronson, Rudolph E Tanzi, Doo Yeon KimAbstract:The "amyloid β hypothesis" of Alzheimer's disease (AD) has been the reigning hypothesis explaining pathogenic mechanisms of AD over the last two decades. However, this hypothesis has not been fully validated in animal models, and several major unresolved issues remain. We recently developed a human Neural Cell culture model of AD based on a three-dimensional (3D) Cell culture system. This unique, Cellular model recapitulates key events of the AD pathogenic cascade, including β-amyloid plaques and neurofibrillary tangles. Our 3D human Neural Cell culture model system provides a premise for a new generation of Cellular AD models that can serve as a novel platform for studying pathogenic mechanisms and for high-throughput drug screening in a human brain-like environment.
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a three dimensional human Neural Cell culture model of alzheimer s disease
Nature, 2014Co-Authors: Se Hoon Choi, Young Hye Kim, Carla Davanzo, Matthias Hebisch, Christopher Sliwinski, Seungkyu Lee, Hechao Chen, Basavaraj Hooli, Caroline Asselin, Julien MuffatAbstract:Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. However, to date, no single disease model has serially linked these two pathological events using human neuronal Cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extraCellular deposition of amyloid-β, including amyloid-β plaques, in a human Neural stem-Cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal Cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human Neural Cell culture system. Our unique strategy for recapitulating Alzheimer's disease pathology in a 3D Neural Cell culture model should also serve to facilitate the development of more precise human Neural Cell models of other neurodegenerative disorders.
Luiza M Higa - One of the best experts on this subject based on the ideXlab platform.
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the cyanobacterial saxitoxin exacerbates Neural Cell death and brain malformations induced by zika virus
PLOS Neglected Tropical Diseases, 2020Co-Authors: Carolina Da S G Pedrosa, Leticia R Q Souza, Tiago A Gomes, Caroline V F De Lima, Pitia Flores Ledur, Karina Karmirian, Jimena Barbeitoandres, Marcelo Do N Costa, Luiza M HigaAbstract:The northeast (NE) region of Brazil commonly goes through drought periods, which favor cyanobacterial blooms, capable of producing neurotoxins with implications for human and animal health. The most severe dry spell in the history of Brazil occurred between 2012 and 2016. Coincidently, the highest incidence of microcephaly associated with the Zika virus (ZIKV) outbreak took place in the NE region of Brazil during the same years. In this work, we tested the hypothesis that saxitoxin (STX), a neurotoxin produced in South America by the freshwater cyanobacteria Raphidiopsis raciborskii, could have contributed to the most severe Congenital Zika Syndrome (CZS) profile described worldwide. Quality surveillance showed higher cyanobacteria amounts and STX occurrence in human drinking water supplies of NE compared to other regions of Brazil. Experimentally, we described that STX doubled the quantity of ZIKV-induced Neural Cell death in progenitor areas of human brain organoids, while the chronic ingestion of water contaminated with STX before and during gestation caused brain abnormalities in offspring of ZIKV-infected immunocompetent C57BL/6J mice. Our data indicate that saxitoxin-producing cyanobacteria is overspread in water reservoirs of the NE and might have acted as a co-insult to ZIKV infection in Brazil. These results raise a public health concern regarding the consequences of arbovirus outbreaks happening in areas with droughts and/or frequent freshwater cyanobacterial blooms.
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the cyanobacterial saxitoxin exacerbates Neural Cell death and brain malformations induced by zika virus
bioRxiv, 2019Co-Authors: Carolina Da S G Pedrosa, Leticia R Q Souza, Tiago A Gomes, Caroline V F De Lima, Pitia Flores Ledur, Karina Karmirian, Jimena Barbeitoandres, Marcelo Do N Costa, Luiza M HigaAbstract:The northeast (NE) region of Brazil commonly goes through drought periods, which favor cyanobacterial blooms, capable of producing neurotoxins with implications for human and animal health. The most severe dry spell in the history of Brazil occurred between 2012 and 2016. Coincidently, the highest incidence of microcephaly associated with the Zika virus (ZIKV) outbreak was described in the NE region of Brazil during the same years. In this work, we tested the hypothesis that saxitoxin (STX), a neurotoxin produced in South America by the freshwater cyanobacteria Raphidiopsis raciborskii, could have contributed to the most severe Congenital Zika Syndrome (CZS) profile described worldwide. Quality surveillance showed higher cyanobacteria amounts and STX occurrence in human drinking water supplies of NE compared to other regions of Brazil. Experimentally, we described that STX doubled the amount of ZIKV-induced Neural Cell death in progenitor areas of human brain organoids, while the chronic ingestion of water contaminated with STX before and during gestation caused brain abnormalities in offspring of ZIKV-infected immunocompetent C57BL/6J mice. Our data indicate that saxitoxin-producing cyanobacteria is overspread in water reservoirs of the NE and might have acted as a co-insult to ZIKV infection in Brazil. These results raise a public health concern regarding the consequences of arbovirus outbreaks happening in areas with droughts and/or frequent freshwater cyanobacterial blooms.