Journal of Neurochemistry

Cover image for Vol. 132 Issue 3

Early View (Online Version of Record published before inclusion in an issue)

Edited By: Jörg Schulz

Impact Factor: 4.244

ISI Journal Citation Reports © Ranking: 2013: 63/252 (Neurosciences); 74/291 (Biochemistry & Molecular Biology)

Online ISSN: 1471-4159

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  1. 1 - 30
  1. Original Articles

    1. CB1-receptor knockout neonatal mice are protected against ethanol-induced impairments of DNMT1, DNMT3A, and DNA methylation

      Nagaraja N. Nagre, Shivakumar Subbanna, Madhu Shivakumar, Delphine Psychoyos and Balapal S. Basavarajappa

      Article first published online: 27 JAN 2015 | DOI: 10.1111/jnc.13006

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      Schematic mechanism of action by which ethanol impairs DNA methylation. Studies have demonstrated that ethanol has the capacity to bring epigenetic changes to contribute to the development of fetal alcohol spectrum disorder (FASD). However, the mechanisms are not well studied. P7 ethanol induces the activation of caspase 3 and impairs DNA methylation through reduced DNA methyltransferases (DNMT1 and DNMT3A) proteins ([RIGHTWARDS ARROW]). The inhibition or genetic ablation of cannabinoid receptor type-1 or inhibition of histone methyltransferase (G9a) by Bix (-----) or inhibition of caspase 3 activation by Q- quinoline-Val-Asp(Ome)-CH2-O-phenoxy (Q-VD-OPh) (image) rescue loss of DNMT1, DNMT3A as well as DNA methylation. Hence, the putative DNMT1/DNMT3A/DNA methylation mechanism may have a potential regulatory role in FASD.

    2. Systemically administered neuregulin-1β1 rescues nigral dopaminergic neurons via the ErbB4 receptor tyrosine kinase in MPTP mouse models of Parkinson's disease

      Candan Depboylu, Thomas W. Rösler, Anderson de Andrade, Wolfgang H. Oertel and Günter U. Höglinger

      Article first published online: 26 JAN 2015 | DOI: 10.1111/jnc.13026

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      Previously, we demonstrated that systemically administered neuregulin-1β1 (Nrg1β1) passes the blood-brain barrier, phosphorylates ErbB4 receptors and elevates dopamine (DA) levels in the nigrostriatal system of healthy mice. Nrg1β1 protects nigral DAergic neurons in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease (PD). Here, we show that Nrg1β1 rescues nigral DAergic neurons also against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced cell death. ErbB4 expression is essential for the neuroprotective effect of Nrg1β1 on midbrain DAergic neurons. Nrg1β1 might be beneficial in PD treatment.

  2. Short Communications

    1. Dopamine transporter oligomerization: impact of combining protomers with differential cocaine analog binding affinities

      Juan Zhen, Tamara Antonio, Shu-Yuan Cheng, Solav Ali, Kymry T. Jones and Maarten E. A. Reith

      Article first published online: 26 JAN 2015 | DOI: 10.1111/jnc.13025

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      The dopamine transporter (DAT) can exist as an oligomer but it is unknown whether the protomers function independently. The present results indicate that protomers that are superpotent or deficient in cocaine analog binding can confer enhanced or reduced potency to the oligomer, respectively. In this respect, positive or negative cooperativity is revealed in the DAT oligomer.

  3. Original Articles

    1. Substantially elevating the levels of αB-crystallin in spinal motor neurons of mutant SOD1 mice does not significantly delay paralysis or attenuate mutant protein aggregation

      Guilian Xu, Susan Fromholt, Jacob I. Ayers, Hilda Brown, Zoe Siemienski, Keith W. Crosby, Christopher A. Mayer, Christopher Janus and David R. Borchelt

      Article first published online: 26 JAN 2015 | DOI: 10.1111/jnc.13022

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      Enhancing the protein chaperone function may present a therapeutic approach to amyotrophic lateral sclerosis caused by mutations in SOD1, and other neurodegenerative disorders characterized by cytosolic protein aggregation. Previous studies in cell models suggested that the chaperone known as αB-crystallin (αB-crys) can prevent mutant SOD1 aggregation. We report that transgenic expression of αB-crys at > 6-fold the normal level in spinal cords of mice expressing mutant SOD1 produces no therapeutic benefit.

    2. Side-chain interactions in the regulatory domain of human glutamate dehydrogenase determine basal activity and regulation

      Vasileios Mastorodemos, Konstantinos Kanavouras, Shobana Sundaram, Maria Providaki, Zoe Petraki, Michael Kokkinidis, Ioannis Zaganas, Diomedes E. Logothetis and Andreas Plaitakis

      Article first published online: 26 JAN 2015 | DOI: 10.1111/jnc.13019

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      Glutamate dehydrogenase (GDH) is central to the metabolism of the excitatory transmitter glutamate, and links it with carbohydrate metabolism in energy homeostasis and cell signaling. The isoform hGDH2, in contrast to hGDH1, is dissociated from GTP (guanosine triphosphate) control, has a reduced basal activity, but remains highly responsive to ADP/L-leucine activation. Substitution of Serine (Ser) for arginine (Arg443) in hGDH1 diminishes basal activity (< 2% of capacity) and abrogates L-leucine activation. We provide evidence that side-chain interactions between 409 and 443 positions in the regulatory domain of GDH are crucial for basal catalytic activity, allosteric regulation, and relative resistance to thermal inactivation.

    3. A novel DYRK1A (Dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro

      Séverine Coutadeur, Hélène Benyamine, Laurence Delalonde, Catherine de Oliveira, Bertrand Leblond, Alicia Foucourt, Thierry Besson, Anne-Sophie Casagrande, Thierry Taverne, Angélique Girard, Matthew P. Pando and Laurent Désiré

      Article first published online: 26 JAN 2015 | DOI: 10.1111/jnc.13018

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      Inhibition of the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a new high-potential therapeutic approach for Alzheimer disease. Here we describe EHT 5372, a novel potent and selective DYRK1A inhibitor. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation, Aβ production and Aβ effects on phospho-Tau, including Tau aggregation.

    4. Susceptibility to excitotoxicity in aged hippocampal cultures and neuroprotection by non-steroidal anti-inflammatory drugs: role of mitochondrial calcium

      María Calvo, Sara Sanz-Blasco, Erica Caballero, Carlos Villalobos and Lucía Núñez

      Article first published online: 26 JAN 2015 | DOI: 10.1111/jnc.13004

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      Rat hippocampal neurons aged in culture were used to investigate mechanisms of age-related susceptibility to excitotoxicity and neuroprotection by non-steroidal anti-inflammatory drugs (NSAIDs). Old neurons display enhanced resting calcium and responses to NMDA along with increased expression of NMDA receptor subunits NR1 and NR2A altogether favoring mitochondrial calcium overload. NSAIDs protect neurons against excitotoxicity acting on mitochondrial calcium uptake. NMDA, N methyl d-aspartate.

    5. Pre-synaptic localization of the γ-secretase-inhibiting protein p24α2 in the mammalian brain

      Lei Liu, Kazunori Fujino and Masaki Nishimura

      Article first published online: 26 JAN 2015 | DOI: 10.1111/jnc.13000

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      The p24 family member p24α2 attenuates amyloid-β (Aβ) generation by inhibiting the γ-secretase processing. We report that p24α2 is condensed at active zone-docked synaptic vesicles in the brain. p24α2 expression is highest in the post-natal period and gradually decreases with age. Our results suggest a novel function for p24α2 at the synapse, including the regulation of brain Aβ generation.

    6. CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs-mediated neuroinflammation in bone cancer rats

      Xue-Ming Hu, Yan-Nan Liu, Hai-Long Zhang, Shou-Bin Cao, Ting Zhang, Li-Ping Chen and Wen Shen

      Article first published online: 26 JAN 2015 | DOI: 10.1111/jnc.12985

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      Following tumor cell inoculation, chemokine CXCL12 from astrocytes spreads around the spinal environment, resulting in functional activation of CXCR4-expressing astrocytes and microglia. Once glia are activated, they may initiate MAPK (mitogen-activated protein kinase) pathways, and subsequently produce proinflammatory cytokines and chemokines. Among them, CXCL12 could reinforce the astrocytic and microglial activation in autocrine and paracrine manners. Such positive feedback loops sustain perseverant neuroinflammation, facilitate glial activation, and finally lead to bone cancer pain. IL = interleukin; TNF = tumor necrosis factor.

    7. Identification of the role of bone morphogenetic protein (BMP) and transforming growth factor-β (TGF-β) signaling in the trajectory of serotonergic differentiation in a rapid assay in mouse embryonic stem cells in vitro

      Atsushi Yamasaki, Atsushi Kasai, Akihiro Toi, Maki Kurita, Saki Kimoto, Atsuko Hayata-Takano, Takanobu Nakazawa, Kazuki Nagayasu, Norihito Shintani, Ryota Hashimoto, Akira Ito, Herbert Y. Meltzer, Yukio Ago, James A. Waschek, Yusuke Onaka, Toshio Matsuda, Akemichi Baba and Hitoshi Hashimoto

      Article first published online: 23 JAN 2015 | DOI: 10.1111/jnc.12999

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      Candidate-based screening for serotonergic induction using a rapid assay in mouse embryonic stem cells revealed that the bone morphogenetic protein (BMP) type I receptor kinase inhibitors selectively induce serotonergic differentiation, whereas the TGF-β receptor inhibitor SB-431542 inhibits the differentiation. These results suggest that inhibition of BMP type I receptors and concomitant activation of transforming growth factor-β (TGF-β) receptor signaling are involved in the early trajectory of serotonergic differentiation.

    8. Different effects of bisphenol-A on memory behavior and synaptic modification in intact and estrogen-deprived female mice

      Xiaohong Xu, Ting Gu and Qiaoqiao Shen

      Article first published online: 23 JAN 2015 | DOI: 10.1111/jnc.12998

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      We showed that bisphenol-A (BPA) improved ovariectomy (Ovx)-induced memory impairment but diminished the rescue effect of estradial on memory of Ovx mice. BPA increased the synaptic density of the Ovx hippocampus, but inhibited the enhancement of estradial on synaptogenesis of Ovx mice. Our findings provided evidence hat BPA interfered with hormonal regulation in synaptic plasticity and memory of female mice as a potent estrogen mimetic and as a disruptor of estrogen under various concentration of cycling estrogen.

    9. Elevated spinal monoamine neurotransmitters after antenatal hypoxia–ischemia in rabbit cerebral palsy model

      Alexander Drobyshevsky, Silvia Honda Takada, Kehuan Luo, Matthew Derrick, Lei Yu, Katharina A. Quinlan, Jeannette Vasquez-Vivar, Maria Inês Nogueira and Sidhartha Tan

      Article first published online: 23 JAN 2015 | DOI: 10.1111/jnc.12997

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      Following prenatal hypoxia–ischemia, newborn rabbits exhibit elevated levels of serotonin in the spinal cord that were linked to muscle hypertonia. Serotonergic terminal density was also increased in hypertonic newborns’ spinal cord. Intrathecal administration of the non-selective serotonin receptor inhibitor methysergide decreased muscle tone in hypertonic newborns only. Elevated spinal serotonin thus suggests a novel pathophysiological mechanism of hypertonia in cerebral palsy.

    10. S-allyl cysteine activates the Nrf2-dependent antioxidant response and protects neurons against ischemic injury in vitro and in vivo

      Huanying Shi, Xu Jing, Xinbing Wei, Ruth G. Perez, Manru Ren, Xiumei Zhang and Haiyan Lou

      Article first published online: 23 JAN 2015 | DOI: 10.1111/jnc.12986

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      The transcription factor Nrf2 is involved in cerebral ischemic disease and may be a promising target for the treatment of stroke. We provide novel evidence that SAC confers neuroprotection against ischemic stroke by activating the antioxidant Nrf2 signaling pathway. ARE, antioxidant response element; GCLC, glutathione cysteine ligase regulatory subunit; GCLM, glutathione cysteine ligase modulatory subunit; HO-1, heme oxygenase-1; JNK, c-Jun N-terminal kinase; Keap1, Kelch-like ECH-associated protein 1; Maf, musculoaponeurotic fibrosarcoma; Nrf2, nuclear factor erythroid-2-related factor 2; SAC, S-allyl cysteine; ROS, reactive oxygen species.

    11. Transcription factors Sox10 and Sox2 functionally interact with positive transcription elongation factor b in Schwann cells

      Juliane Arter and Michael Wegner

      Article first published online: 22 JAN 2015 | DOI: 10.1111/jnc.13013

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      Sox transcription factors are important regulators of nervous system development. While they are known to regulate transcription by recruiting and stabilizing the RNA polymerase II preinitiation complex directly or with help of the Mediator complex, this study provides evidence that Sox10 and Sox2 additionally influence transcription in glial cells at the elongation stage by recruiting P-TEFb. Cdk9, cyclin-dependent kinase 9; P-TEFb, positive transcription elongation factor b; Pol II, RNA polymerase II; Sox, Sox2 or Sox10 protein.

    12. ABCD1 deletion-induced mitochondrial dysfunction is corrected by SAHA: implication for adrenoleukodystrophy

      Mauhamad Baarine, Craig Beeson, Avtar Singh and Inderjit Singh

      Article first published online: 13 JAN 2015 | DOI: 10.1111/jnc.12992

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      Schematic description of the effects of loss of peroxisomal ATP-binding cassette transporter D1 (ABCD1) gene on cellular Redox and mitochondrial activities and their correction by suberoylanilide hydroxamic acid (SAHA) treatment. Pathogenomic accumulation of very long chain fatty acids (VLCFA) as a result of loss of ABCD1 leads to dysfunctions of mitochondrial biogenesis and its activities. Treatment with SAHA corrects mitochondrial dysfunctions. These studies describe unique cooperation between mitochondria and peroxisome for cellular activities.

    13. Pre-synaptic C-terminal truncated tau is released from cortical synapses in Alzheimer's disease

      Sophie Sokolow, Kristen M. Henkins, Tina Bilousova, Bianca Gonzalez, Harry V. Vinters, Carol A. Miller, Lindsey Cornwell, Wayne W. Poon and Karen H. Gylys

      Article first published online: 13 JAN 2015 | DOI: 10.1111/jnc.12991

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      Results demonstrate the abundance of tau, mainly C-terminal truncated tau, in synaptic terminals in aged control and in Alzheimer's disease (AD) samples. Tau fragments and dimers/oligomers are prominent in AD synapses. Following depolarization, tau release is potentiated in AD nerve terminals compared to aged controls. We hypothesize (i) endosomal release of the different tau peptides from AD synapses, and (ii) together with phosphorylation, fragmentation of synaptic tau exacerbates tau aggregation, synaptic dysfunction, and the spread of tau pathology in AD. Aβ = amyloid-beta.

    14. Loss of mitofusin 2 links beta-amyloid-mediated mitochondrial fragmentation and Cdk5-induced oxidative stress in neuron cells

      Junghyung Park, Hoonsung Choi, Ju-Sik Min, Bokyung Kim, Sang-Rae Lee, Jong Won Yun, Myung-Sook Choi, Kyu-Tae Chang and Dong-Seok Lee

      Article first published online: 13 JAN 2015 | DOI: 10.1111/jnc.12984

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      Mitochondrial fragmentation induced by amyloid-beta oligomer (AβOs) which is generated from the Swedish mutation of amyloid precursor protein (APP) accompanies reduced Mfn1/2 levels. Interestingly, the Cdk5 pathway, including phosphorylation of the Prx2-related oxidative stress, has been shown to regulate Mfn1/2. Furthermore, Mfn2 over-expression significantly inhibits the AβO-mediated neuronal cells death pathway, but not Mfn1 over-expression. Therefore, these results indicate that AβO-mediated oxidative stress triggers mitochondrial fragmentation via decreased Mfn2 expression by activating Cdk5-induced Prx2 phosphorylation. ATP, adenosine triphosphate; Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma 2; Cdk5, Cyclin-dependent kinase; Cyt C, cytochrome C; Mfn2, mitofusin 2; Prx2, peroxiredoxin 2; ROS, reactive oxygen species.

    15. The metabolic impact of β-hydroxybutyrate on neurotransmission: Reduced glycolysis mediates changes in calcium responses and KATP channel receptor sensitivity

      Trine M. Lund, Kenneth B. Ploug, Anne Iversen, Anders A. Jensen and Inger Jansen-Olesen

      Article first published online: 13 JAN 2015 | DOI: 10.1111/jnc.12975

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      Energy metabolism and neurotransmission are linked and involve ATP-sensitive potassium (KATP) channels. However, it is still unclear how and to what degree available energy substrate affects this link. We investigated the effect of changing energy substrate from only glucose to a combination of glucose and R-β-hydroxybutyrate in cultured neurons. Using the latter combination, glycolysis was diminished, NMDA receptor-induced calcium responses were lower, and the KATP channel blocker glibenclamide caused a higher transmitter release.

    16. Differential effects of lipopolysaccharide on energy metabolism in murine microglial N9 and cholinergic SN56 neuronal cells

      Joanna Klimaszewska-Łata, Sylwia Gul-Hinc, Hanna Bielarczyk, Anna Ronowska, Marlena Zyśk, Katarzyna Grużewska, Tadeusz Pawełczyk and Andrzej Szutowicz

      Article first published online: 4 JAN 2015 | DOI: 10.1111/jnc.12979

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      There are significant differences between acetyl-CoA and ATP levels and enzymes of acetyl-CoA metabolism in non-activated microglial N9 and non-differentiated cholinergic SN56 neuroblastoma cells. Pathological stimulation of microglial toll-like receptors (TLRs) triggered excessive synthesis of microglia-derived nitric oxide (NO)/NOO radicals that endogenously inhibited pyruvate dehydrogenase complex (PDHC), aconitase, and α-ketoglutarate dehydrogenase complex. However, it caused none or small suppressions of acetyl-CoA and microglial viability, respectively. Microglia-derived NO inhibited same enzymes in cholinergic neuronal cells causing marked viability loss because of acetyl-CoA deficits evoked by its competitive consumption by energy producing and acetylcholine/N-acetyl-l-aspartate (NAA) synthesizing pathways.

    17. You have free access to this content
      Cleaning up after ICH: the role of Nrf2 in modulating microglia function and hematoma clearance

      Xiurong Zhao, Guanghua Sun, Shun-Ming Ting, Shen Song, Jie Zhang, Nancy J. Edwards and Jaroslaw Aronowski

      Article first published online: 24 NOV 2014 | DOI: 10.1111/jnc.12974

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      Microglia/Macrophages (MMφ) utilize the scavenger receptor CD36 to internalize the red blood cells (RBC) during the hematoma cleanup process after intracerebral hemorrhage (ICH). During RBC catabolism in phagosomes of MMφ, reactive oxygen species (ROS) are generated causing oxidative stress and injury to the phagocyte and the neurovascular unit. We propose that the treatment of MMφ with Nrf2 agonist (sulforaphane) could:(1) speed up the phagocytosis process by up-regulating CD36 expression, and (2) improve MMΦ resistant to oxidative damage by up-regulating the expression of antioxidative enzymes such as catalase (Cat) or superoxide dismutase-1 (SOD).

    18. The anticonvulsant actions of carisbamate associate with alterations in astrocyte glutamine metabolism in the lithium–pilocarpine epilepsy model

      Mussie Ghezu Hadera, Jean-Baptiste Faure, Nina Berggaard, Tesfaye Wolde Tefera, Astrid Nehlig and Ursula Sonnewald

      Article first published online: 17 NOV 2014 | DOI: 10.1111/jnc.12977

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      To understand the metabolic basis of the strong neuroprotection and reduction in seizure severity caused by carisbamate (CRS) in the lithium–pilocarpine (Li-Pilo) model of temporal lobe epilepsy (TLE), we injected CRS for 7 days starting 1 h after status epilepticus and 2 months later [1-13C]glucose and [1,2-13C]acetate. 13C Magnetic resonance spectroscopy analysis was performed on brain extracts and we found that CRS prevented reduction in neuronal mitochondrial metabolism but its effect on astrocytes was likely key in determining outcome of treatment in this model. ALE = absence like epilepsy; acetyl CoA = acetyl coenzyme A; GS = glutamine synthetase; PAG = phosphate activated glutaminase; PC = pyruvate carboxylase; OAA = oxaloacetate; TCA cycle = tricarboxylic acid cycle.

    19. Inositol synthesis regulates the activation of GSK-3α in neuronal cells

      Cunqi Ye and Miriam L. Greenberg

      Article first published online: 17 NOV 2014 | DOI: 10.1111/jnc.12978

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      Inositol is an essential metabolite that serves as a precursor for inositol lipids and inositol phosphates. We report that inhibition of the rate-limiting enzyme of inositol synthesis leads to the inactivation of glycogen synthase kinase (GSK) 3α by increasing inhibitory phosphorylation of this kinase. These findings have implications for the therapeutic mechanisms of mood stabilizers and suggest that inositol synthesis and GSK 3α activity are intrinsically related.

    20. Hypoxia interferes with aryl hydrocarbon receptor pathway in hCMEC/D3 human cerebral microvascular endothelial cells

      Aude Jacob, Sophie Potin, Bruno Saubaméa, Dominique Crete, Jean-Michel Scherrmann, Emmanuel Curis, Carole Peyssonnaux and Xavier Declèves

      Article first published online: 14 NOV 2014 | DOI: 10.1111/jnc.12972

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      We studied the putative crosstalk of AhR and hypoxia pathways in hCMEC/D3 human cerebral microvascular endothelial cells. While hypoxia decreased the expression of the two AhR target genes CYP1A1 and CYP1B1, AhR activation results in no change in hypoxia target gene expression. This is the first sign of AhR and hypoxia pathway crosstalk in an in vitro model of the human cerebral endothelium.

    21. Coordinated activation of AMP-activated protein kinase, extracellular signal-regulated kinase, and autophagy regulates phorbol myristate acetate-induced differentiation of SH-SY5Y neuroblastoma cells

      Nevena Zogovic, Gordana Tovilovic-Kovacevic, Maja Misirkic-Marjanovic, Ljubica Vucicevic, Kristina Janjetovic, Ljubica Harhaji-Trajkovic and Vladimir Trajkovic

      Article first published online: 14 NOV 2014 | DOI: 10.1111/jnc.12980

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      Phorbol myristate acetate (PMA) induces the expression of dopamine transporter, microtubule-associated protein 2, and β-tubulin, and subsequent neuronal differentiation of SH-SY5Y neuroblastoma cells through AMP-activated protein kinase (AMPK)-dependent activation of extracellular signal-regulated kinase (ERK). The activation of AMPK/ERK axis also induces the expression of beclin-1 and Atg7, and increases LC3 conversion, thereby triggering the autophagic response that counteracts differentiation process.

    22. E2F1 in neurons is cleaved by calpain in an NMDA receptor-dependent manner in a model of HIV-induced neurotoxicity

      Jacob W. Zyskind, Ying Wang, Giyong Cho, Jenhao H. Ting, Dennis L. Kolson, David R. Lynch and Kelly L. Jordan-Sciutto

      Article first published online: 10 NOV 2014 | DOI: 10.1111/jnc.12956

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      After crossing the blood–brain barrier, HIV-infected monocytes differentiate into macrophages and release excitotoxins and inflammatory factors including glutamate into the brain parenchyma (1). These factors stimulate neuronal N-Methyl-d-aspartate (NMDA) receptors (2), causing calcium influx (3) and subsequent activation of the cysteine protease calpain (4). Activated calpain cleaves multiple substrates including E2F1, producing a stabilized protein fragment with truncations at the N- and C-terminus (5). Calpain-cleaved E2F1 may contribute to calpain-mediated neuronal damage observed in NMDA receptor-mediated neurotoxicity (6).

    23. Nuclear diacylglycerol lipase-α in rat brain cortical neurons: evidence of 2-arachidonoylglycerol production in concert with phospholipase C-β activity

      Gontzal García del Caño, Xabier Aretxabala, Imanol González-Burguera, Mario Montaña, Maider López de Jesús, Sergio Barrondo, Ramón J. Barrio, Carmen Sampedro, M. Arantzazu Goicolea and Joan Sallés

      Article first published online: 31 OCT 2014 | DOI: 10.1111/jnc.12963

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      We report that phosphatidylinositol-phospholipase C (PtdIns-PLC) and diacylglycerol lipase (DAGL) activities are co-compartmentalized in isolated adult cortical neuronal nuclei, leading to a nuclear-localized production of the endocannabinoid 2-AG. Our results provide biochemical grounds to hypothesize a role for 2-AG locally produced within the neuronal nucleus. 2-AG, 2-arachidonoylglycerol; AA, arachidonic acid; ABHD6, α-β-hydrolase domain-6; COX-2, cyclooxygenase-2; DAGK, diacylglycerol kinase; DAGs, diacylglycerols; LPP, lipid phosphate phosphatase; MAGL, monoacylglycerol lipase; NAM, N-arachidonoylmaleimide; PA, phosphatidic acid; PGG2-G, prostaglandin G2-glycerol; PLD, phospholipase D; PtdCho, phosphatidylcholine; PtdInsP2, phosphatidylinositol-4,5-bisphosphate; THL, tetrahydrolipstatin.

    24. Tolfenamic acid reduces tau and CDK5 levels: implications for dementia and tauopathies

      Lina Adwan, Gehad M. Subaiea, Riyaz Basha and Nasser H. Zawia

      Article first published online: 18 OCT 2014 | DOI: 10.1111/jnc.12960

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      A new approach for targeting Alzheimer's disease through a transcriptional based mechanism is presented. Tolfenamic acid lowers the levels of tau, which forms pathological aggregates in Alzheimer's disease and other tauopathies, by promoting the degradation of the transcription factor specificity protein 1 which regulates tau transcription.

    25. Astrocytes mediate HIV-1 Tat-induced neuronal damage via ligand-gated ion channel P2X7R

      Manju Tewari,   Monika, Rebu K Varghese, Malini Menon and Pankaj Seth

      Article first published online: 18 OCT 2014 | DOI: 10.1111/jnc.12953

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      We investigated the role of P2X7R in Tat-mediated neuroinflammation and neuronal damage. We proposed the following cascade for Tat-mediated CCL2 release from astrocytes: Tat mediates increase in P2X7R expression, which on activation evokes increase in intracellular calcium, which further leads to phosphorylation of ERK1/2 followed by the release of CCL2 from astrocytes. Tat also leads to direct and indirect (mediated via astrocytes) neuronal death that can be abrogated by inhibiting P2X7R. We believe that these finding should provide new insights into the role of astrocytes in HIV-1 Tat-mediated neurotoxicity.

    26. S-nitrosoglutathione prevents blood–brain barrier disruption associated with increased matrix metalloproteinase-9 activity in experimental diabetes

      Aanchal Aggarwal, Alka Khera, Inderjit Singh and Rajat Sandhir

      Article first published online: 17 OCT 2014 | DOI: 10.1111/jnc.12939

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      Hyperglycemia is known to induce microvascular complications, thereby altering blood–brain barrier (BBB) permeability. In the present study, we have shown that this effect occurred through increased matrix metalloproteinase 9 (MMP-9) and decreased tissue inhibitor of matrix metalloproteinase (TIMP-1) levels, leading to cognitive deficits. S-nitrosoglutathione (GSNO) was able to abridge MMP-9 activation and TIMP-1 levels, thereby restoring BBB integrity and improving learning and memory. GSNO could thus be beneficial in hyperglycemia-induced encephalopathy. STZ, Streptozotocin.

    27. Revisiting the peripheral sink hypothesis: inhibiting BACE1 activity in the periphery does not alter β-amyloid levels in the CNS

      Biljana Georgievska, Susanne Gustavsson, Johan Lundkvist, Jan Neelissen, Susanna Eketjäll, Veronica Ramberg, Tjerk Bueters, Karin Agerman, Anders Juréus, Samuel Svensson, Stefan Berg, Johanna Fälting and Urban Lendahl

      Article first published online: 18 SEP 2014 | DOI: 10.1111/jnc.12937

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      Aggregation of amyloid beta (Aβ) peptides in the brain is a central aspect of Alzheimer's disease. In this study, we demonstrate that inhibition of Aβ formation by BACE1 inhibitors needs to be carried out in the brain and that reduction of Aβ in the periphery is not sufficient to reduce brain Aβ levels. This information is useful for developing future Aβ-targeting therapies for Alzheimer's disease.

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