Journal of Neurochemistry

Cover image for Vol. 129 Issue 4

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

Edited By: Jörg Schulz

Impact Factor: 3.973

ISI Journal Citation Reports © Ranking: 2012: 71/252 (Neurosciences); 83/290 (Biochemistry & Molecular Biology)

Online ISSN: 1471-4159

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  1. Editorial Highlights

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      Novel role of glial syntaxin-1B in supporting neuronal survival

      Seungmee Park, Na-Ryum Bin and Shuzo Sugita

      Article first published online: 22 APR 2014 | DOI: 10.1111/jnc.12723

      Read the full article ‘HPC-1/syntaxin 1A and syntaxin 1B play distinct roles in neuronal survival’ on doi: 10.1111/jnc.12722

  2. Original Articles

    1. Evidence for an angiotensin-(1-7) neuropeptidase expressed in the brain medulla and CSF of sheep

      Allyson C. Marshall, Nancy T. Pirro, James C. Rose, Debra I. Diz and Mark C. Chappell

      Article first published online: 19 APR 2014 | DOI: 10.1111/jnc.12720

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      Angiotensin-(1-7) actions are mediated by the AT7/Mas receptor and include reduced blood pressure, decreased oxidative stress, enhanced baroreflex sensitivity, and increased nitric oxide (NO). Ang-(1-7) is directly formed from Ang I by neprilysin (NEP). We identify a new pathway for Ang-(1-7) metabolism in the brain distinct from angiotensin-converting enzyme-dependent hydrolysis. The Ang-(1-7) endopeptidase (A7-EP) degrades the peptide to Ang-(1-4) and may influence central Ang-(1-7) tone.

  3. Reviews

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      Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects

      Robert Vassar, Peer-Hendrik Kuhn, Christian Haass, Matthew E. Kennedy, Lawrence Rajendran, Philip C. Wong and Stefan F. Lichtenthaler

      Article first published online: 19 APR 2014 | DOI: 10.1111/jnc.12715

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      The protease BACE1 is a major drug target in Alzheimer disease. Together with its homolog BACE2, both proteases have an increasing number of functions within and outside of the nervous system. This review highlights recent progress in understanding cell biology, substrates, and functions of BACE proteases and discusses the therapeutic options and potential mechanism-based liabilities, in particular for BACE inhibitors in Alzheimer disease.

  4. Original Articles

    1. HIV-1 protein Tat produces biphasic changes in NMDA-evoked increases in intracellular Ca2+ concentration via activation of Src kinase and nitric oxide signaling pathways

      Kelly A. Krogh, Nicole Wydeven, Kevin Wickman and Stanley A. Thayer

      Article first published online: 19 APR 2014 | DOI: 10.1111/jnc.12724

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      HIV-associated neurocognitive disorders (HAND) afflict about half of HIV-infected patients. HIV-infected cells shed viral proteins, such as the transactivator of transcription (Tat), which can cause neurotoxicity by over activation of NMDA receptors (NMDARs). We show that HIV-1 Tat evoked biphasic changes in NMDA-evoked [Ca2+]i responses. Initially, Tat potentiated NMDA-evoked responses following LRP-mediated activation of Src kinase. Subsequently, Tat-induced NMDAR potentiation adapted by activation of a NOS/sGC/PKG pathway that attenuated NMDA-evoked increases in [Ca2+]i. Adaptation may be a novel neuroprotective mechanism to prevent excessive Ca2+ influx. Solid and dashed arrows represent direct and potentially indirect connections, respectively.

    2. Impairments of long-term depression induction and motor coordination precede Aβ accumulation in the cerebellum of APPswe/PS1dE9 double transgenic mice

      Yuki Kuwabara, Masato Ishizeki, Naoto Watamura, Junya Toba, Aya Yoshii, Takafumi Inoue and Toshio Ohshima

      Article first published online: 19 APR 2014 | DOI: 10.1111/jnc.12728

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      APPswe/PS1d9E mice, a commonly used Alzheimer's mouse model, have Aβ plaques in the cerebellum after 8 months old. We show that soluble Aβ impairs LTD induction in the cerebellar slice. APPswe/PS1d9E mice demonstrate defects of motor coordination and LTD induction in the cerebellum at the pre-Aβ accumulation period.

    3. Mephedrone alters basal ganglia and limbic neurotensin systems

      Christopher L. German, Amanda H. Hoonakker, Annette E. Fleckenstein and Glen R. Hanson

      Article first published online: 19 APR 2014 | DOI: 10.1111/jnc.12727

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      This study evaluated the effects of mephedrone upon the neuropeptide neurotensin (NT) – an inhibitory feedback of dopamine signaling – within the basal ganglia and limbic system of the central nervous system as well as the role of NT in mephedrone self-administration. Mephedrone increased NT tissue content, which corresponds to reduced NT release and signaling, and NT receptor agonist treatment reduces mephedrone self-administration, suggesting drug consumption behavior may be tied to the loss of NT signaling.

  5. Reviews

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      mTOR complex 1: a key player in neuroadaptations induced by drugs of abuse

      Jeremie Neasta, Segev Barak, Sami Ben Hamida and Dorit Ron

      Article first published online: 19 APR 2014 | DOI: 10.1111/jnc.12725

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      Recent studies suggesting that exposure to diverse classes of drugs of abuse as well as exposure to drug-associated memories lead to mTORC1 kinase activation in the limbic system. In turn, mTORC1 controls the onset and the maintenance of pathological neuroadaptions that underlie several features of drug addiction such as drug seeking and relapse. Therefore, we propose that targeting mTORC1 and its effectors is a promising strategy to treat drug disorders.

  6. Original Articles

    1. HPC-1/syntaxin 1A and syntaxin 1B play distinct roles in neuronal survival

      Takefumi Kofuji, Tomonori Fujiwara, Masumi Sanada, Tatsuya Mishima and Kimio Akagawa

      Article first published online: 19 APR 2014 | DOI: 10.1111/jnc.12722

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      Syntaxin 1A (STX1A) and syntaxin 1B (STX1B) are thought to have similar functions as SNARE proteins. However, we found that STX1A and STX1B play distinct roles in neuronal survival using STX1A−/− mice and STX1B−/− mice. STX1B was important for neuronal survival, possibly by regulating the secretion of neurotrophic factors, such as BDNF, from glial cells.

    2. Cortical-layer-specific effects of PACAP and tPA on interneuron migration during post-natal development of the cerebellum

      Emilie Raoult, Magalie Bénard, Hitoshi Komuro, Alexis Lebon, Denis Vivien, Alain Fournier, Hubert Vaudry, David Vaudry and Ludovic Galas

      Article first published online: 19 APR 2014 | DOI: 10.1111/jnc.12714

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      Crucial role of tissue plasminogen activator (tPA) in interneuron migration. Interneuron migration is a critical step for normal establishment of neuronal network. This study indicates that, in the post-natal cerebellum, tPA facilitates the opposite migration of immature excitatory granule neurons (GN) and immature inhibitory basket/stellate cells (B/SC) along the same migratory route. These data show that tPA exerts a pivotal role in neurodevelopment.

    3. α6β2*-subtype nicotinic acetylcholine receptors are more sensitive than α4β2*-subtype receptors to regulation by chronic nicotine administration

      Michael J. Marks, Sharon R. Grady, Outi Salminen, Miranda A. Paley, Charles R. Wageman, J. Michael McIntosh and Paul Whiteaker

      Article first published online: 19 APR 2014 | DOI: 10.1111/jnc.12721

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      This study examined dose–response relationships for murine α6β2*-nicotinic acetylcholine receptor (nAChR) down-regulation by chronic nicotine treatment. The ID50 value for α6β2* down-regulation (35 nM) is ≈ 3x lower than the ED50 value for α4β2* nAChR up-regulation (95 nM), both well within the range reached by human smokers. Chronic nicotine treatment altered α6β2*- and α4β2*-nAChR-mediated [3H]-dopamine release from striatal and olfactory tubercle synaptosomes, but dopaminergic parameters were largely unaffected. We conclude that functional changes are primarily driven by altered nAChR activity.

    4. A mutation protective against Alzheimer's disease renders amyloid β precursor protein incapable of mediating neurotoxicity

      Yuichi Hashimoto and Masaaki Matsuoka

      Article first published online: 9 APR 2014 | DOI: 10.1111/jnc.12717

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      The A598T mutation of amyloid precursor protein APP is linked to a reduction in the incidence rate of Alzheimer's disease (AD). This study shows that TGFβ2 causes death in neuronal cells expressing wild-type APP, but not in those expressing the AD-protective mutant of APP, suggesting that the AD-protective mutation of APP reduces the incidence rate of AD by attenuating the APP-mediated intracellular death signal.

    5. 3D Electrospun scaffolds promote a cytotrophic phenotype of cultured primary astrocytes

      Chew L. Lau, Michelle Kovacevic, Tine S. Tingleff, John S. Forsythe, Holly S. Cate, Daniel Merlo, Cecilia Cederfur, Francesca L. Maclean, Clare L. Parish, Malcolm K. Horne, David R. Nisbet and Philip M. Beart

      Article first published online: 9 APR 2014 | DOI: 10.1111/jnc.12702

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      Astrocytes exist in phenotypes with pro-survival and destructive components, and their biology can be modulated by changing phenotype. Our findings demonstrate murine astrocytes adopt a healthy phenotype when cultured in 3D. Astrocytes proliferate and extend into poly-ε-caprolactone scaffolds displaying 3D stellated morphologies with reduced GFAP expression and actin stress fibres, plus a cytotrophic gene profile. Bioengineered 3D scaffolds have potential to direct inflammation to aid regenerative neurobiology.

    6. The enzyme lecithin-cholesterol acyltransferase esterifies cerebrosterol and limits the toxic effect of this oxysterol on SH-SY5Y cells

      Valeria La Marca, Maria Stefania Spagnuolo, Luisa Cigliano, Daniela Marasco and Paolo Abrescia

      Article first published online: 2 APR 2014 | DOI: 10.1111/jnc.12713

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      24-hydroxycholesterol (24(S)OH-C) is neurotoxic. The enzyme lecithin-cholesterol acyltransferase (LCAT) synthesizes monoesters of 24(S)OH-C in reaction mixtures with proteoliposomes containing phospholipids and apolipoprotein A-I or apolipoprotein E. The esters, also produced by incubation of cerebrospinal fluid only with tritiated 24(S)OH-C, are embedded into lipoproteins that do not enter neurons in culture. The enzyme activity limits the toxicity of 24-hydroxycholesterol in neuron culture.

    7. Mechanical stimulation evokes rapid increases in extracellular adenosine concentration in the prefrontal cortex

      Ashley E. Ross, Michael D. Nguyen, Eve Privman and B. Jill Venton

      Article first published online: 2 APR 2014 | DOI: 10.1111/jnc.12711

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      We have discovered immediate changes in adenosine concentration in the prefrontal cortex following mechanical stimulation. The adenosine increase lasts only about 20 s. Mechanically stimulated adenosine was activity dependent and mostly because of extracellular ATP metabolism. This rapid, transient increase in adenosine may help protect tissue and would occur during implantation of any electrode, such as during deep brain stimulation.

    8. Stable over-expression of the 2-oxoglutarate carrier enhances neuronal cell resistance to oxidative stress via Bcl-2-dependent mitochondrial GSH transport

      Heather M. Wilkins, Samantha Brock, Josie J. Gray and Daniel A. Linseman

      Article first published online: 2 APR 2014 | DOI: 10.1111/jnc.12709

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      Stable over-expression of the 2-oxoglutarate carrier (OGC) in a motor neuronal cell line induced a specific increase in mitochondrial GSH and markedly enhanced resistance to oxidative stress. Over-expression of OGC also induced Bcl-2 expression which was owing to the specific increase in mitochondrial GSH. Intriguingly, enhanced expression of Bcl-2 was required to sustain OGC-dependent GSH transport into the mitochondria. Thus, OGC and Bcl-2 work in a concerted manner to maintain the mitochondrial GSH pool which is crucial for neuronal survival.

    9. 2-Methoxyestradiol confers neuroprotection and inhibits a maladaptive HIF-1α response after traumatic brain injury in mice

      Eva-Verena Schaible, Julia Windschügl, Wiesia Bobkiewicz, Yordan Kaburov, Larissa Dangel, Tobias Krämer, Changsheng Huang, Anne Sebastiani, Clara Luh, Christian Werner, Kristin Engelhard, Serge C. Thal and Michael K.E. Schäfer

      Article first published online: 2 APR 2014 | DOI: 10.1111/jnc.12708

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      We examined neuroprotective effects of 2-methoxyestradiol (2ME2) and the hypoxia-inducible factor 1-α (HIF-1α) response following traumatic brain injury in mice. Early 2ME2 administration reduced the secondary brain damage and neuronal HIF-1α probably involving ubiquitin proteasome system-mediated degradation. The up-regulation of neuropathological HIF-1α target genes and pro-apoptotic BNIP3 protein was attenuated. We propose that the inhibition of a maladaptive HIF-1α response may contribute to 2ME2-mediated neuroprotection.

    10. Down-regulation of serum gonadotropins but not estrogen replacement improves cognition in aged-ovariectomized 3xTg AD female mice

      Russell Palm, Jaewon Chang, Jeffrey Blair, Yoelvis Garcia-Mesa, Hyoung-gon Lee, Rudy J. Castellani, Mark A. Smith, Xiongwei Zhu and Gemma Casadesus

      Article first published online: 2 APR 2014 | DOI: 10.1111/jnc.12706

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      In the aged triple transgenic Alzheimer's disease (AD) mouse model (3xAD-Tg), estrogen replacement after ovariectomy does not improve cognitive function, increases phosphorylated Tau levels and decreases inhibition of GSK3 beta. Luprolide acetate rescues ovariectomy-dependent cognitive function, increases signaling events associated with synaptic plasticity including GSK3 beta inhibition, but does not alter AD pathology. In the human AD female brain, luteinizing hormone (LH) mRNA levels are reduced. In the 3XAD-tg model, brain LH protein levels are reduced by ovariectomy and normalized by leuprolide acetate treatment. These treatment-dependent normalization of LH positively correlates with markers of neuroplasticity and cognitive improvement.

    11. Alterations in STriatal-Enriched protein tyrosine Phosphatase expression, activation, and downstream signaling in early and late stages of the YAC128 Huntington's disease mouse model

      Clare M. Gladding, Jing Fan, Lily Y. J. Zhang, Liang Wang, Jian Xu, Edward H. Y. Li, Paul J. Lombroso and Lynn A. Raymond

      Article first published online: 2 APR 2014 | DOI: 10.1111/jnc.12700

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      The YAC128 Huntington's disease mouse model shows early, enhanced susceptibility to NMDA receptor-mediated striatal apoptosis, progressing to late-stage excitotoxicity resistance. This study shows that elevated NMDA receptor–PSD-95 interactions as well as decreased extrasynaptic STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61) activation may contribute to early enhanced apoptotic signaling. In late-stage YAC128 mice, reduced STEP61 levels and activity correlate with elevated MAPK signaling, consistent with excitotoxicity resistance. Solid and dotted arrows indicate conclusions drawn from the current study and other literature, respectively.

  7. Editorial Highlights

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      A role for SNAREs in neuronal survival?

      Callista B. Harper, Adekunle T. Bademosi, Elizabeth J. Coulson and Frederic A. Meunier

      Article first published online: 2 APR 2014 | DOI: 10.1111/jnc.12699

      Read the full article ‘Botulinum protease-cleaved snare fragments induce cytotoxicity in neuroblastoma cells’ on doi: 10.1111/jnc.12645.

  8. Original Articles

    1. Contribution of cysteine aminotransferase and mercaptopyruvate sulfurtransferase to hydrogen sulfide production in peripheral neurons

      Ryo Miyamoto, Ken-ichi Otsuguro, Soichiro Yamaguchi and Shigeo Ito

      Article first published online: 27 MAR 2014 | DOI: 10.1111/jnc.12698

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      In the peripheral nervous system, hydrogen sulfide (H2S) has been implicated in neurogenic pain or hyperalgesia. This study provides evidence that H2S is synthesized in peripheral neurons through two mitochondrial enzymes, cysteine aminotransferase (CAT) and mercaptopyruvate sulfurtransferase (MPST). We propose that mitochondrial metabolism plays key roles in the physiology and pathophysiology of the peripheral nervous system via regulation of neuronal H2S production.

    2. Matrix metalloproteinase 2 and membrane type 1 matrix metalloproteinase co-regulate axonal outgrowth of mouse retinal ganglion cells

      Djoere Gaublomme, Tom Buyens, Lies De Groef, Michelle Stakenborg, Els Janssens, Signe Ingvarsen, Astrid Porse, Niels Behrendt and Lieve Moons

      Article first published online: 27 MAR 2014 | DOI: 10.1111/jnc.12703

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      Axonal regeneration in the central nervous system is lacking in adult mammals, thereby impeding recovery from injury to the nervous system. Matrix metalloproteinases (MMPs) constitute a family of zinc-dependent proteases that were sporadically reported to influence axon outgrowth. Inhibition of specific MMPs reduced neurite outgrowth from mouse retinal explants. Our data indicate MMP-2 and MT1-MMP as promising axonal outgrowth-promoting molecules and show a possible link between MMP-2 and β1-integrin in axon outgrowth.

    3. Hydrogen sulfide protects blood–brain barrier integrity following cerebral ischemia

      Yali Wang, Jia Jia, Guizhen Ao, Lifang Hu, Hui Liu, Yunqi Xiao, Huaping Du, Nabil J. Alkayed, Chun-Feng Liu and Jian Cheng

      Article first published online: 27 MAR 2014 | DOI: 10.1111/jnc.12695

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      To determine H2S effects on blood–brain barrier (BBB) disruption following stroke, we used two structurally unrelated H2S donors ADT and NaHS. Both ADT and NaHS remarkably protected BBB integrity following experimental stroke. The slow-releasing donor ADT also reduced post-ischemic inflammation-induced expression and activity of MMP9 and NOX4 in the ischemic brain possibly by inhibiting NF-κB activation.

    4. Inhibition of striatal-enriched tyrosine phosphatase 61 in the dorsomedial striatum is sufficient to increased ethanol consumption

      Emmanuel Darcq, Sami Ben Hamida, Su Wu, Khanky Phamluong, Viktor Kharazia, Jian Xu, Paul Lombroso and Dorit Ron

      Article first published online: 27 MAR 2014 | DOI: 10.1111/jnc.12701

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      We show that ethanol-mediated inhibition of STEP61 in the DMS leads to Fyn activation and GluN2B phosphorylation. (a) Under basal conditions, active STEP61 inhibits Fyn activity and dephosphorylates GluN2B. (b) Ethanol leads to the phosphorylation of STEP61 on a specific inhibitory site. The inhibition of STEP61 activity contributes to the activation of Fyn in response to ethanol, which, in turn, phosphorylates GluN2B. These molecular adaptations in the DMS promote ethanol drinking.

    5. Targeted inhibition of KCa3.1 attenuates TGF-β-induced reactive astrogliosis through the Smad2/3 signaling pathway

      Zhihua Yu, Panpan Yu, Hongzhuan Chen and Herbert M. Geller

      Article first published online: 27 MAR 2014 | DOI: 10.1111/jnc.12710

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      Reactive astrogliosis is characterized by the expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycans. We demonstrate that either pharmacological blockade or knockout of KCa3.1 channels reduces reactive gliosis in cultured astrocytes caused by TGF-β, and also reduces TGF-β-induced phosphorylation of Smad2/3.

    6. Cyr61 activates retinal cells and prolongs photoreceptor survival in rd1 mouse model of retinitis pigmentosa

      Joanna Kucharska, Patricia del Río, Blanca Arango-Gonzalez, Matteo Gorza, Annette Feuchtinger, Stefanie M. Hauck and Marius Ueffing

      Article first published online: 27 MAR 2014 | DOI: 10.1111/jnc.12704

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      We propose the following model of Cyr61 neuroprotection within the retina: Cyr61 stimulates retinal Müller glial (RMG) and retinal pigment epithelium (RPE) cells and activates PI3K/Akt, mitogen-activated protein kinase(MAPK)/Erk and Janus kinase(JAK)/Stat-signalling pathways in these cells. Phosphorylated Stat3 and Erk1/2 presumably translocate to the nucleus, induce transcriptional changes, which increase secretion of neuroprotective agents that protect photoreceptors (PR) from mutation-induced death.

  9. Editorial Highlights

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      Making sense of the amyloid precursor protein: its tail tells an interesting tale

      Roberto Cappai

      Article first published online: 27 MAR 2014 | DOI: 10.1111/jnc.12707

      Read the full article ‘The Aβ -clearance protein transthyretin, like neprilysin, is epigenetically regulated by the amyloid precursor protein intracellular domain’ on doi: 10.1111/jnc.12680

  10. Original Articles

    1. Proton-dependent zinc release from intracellular ligands

      Lech Kiedrowski

      Article first published online: 27 MAR 2014 | DOI: 10.1111/jnc.12712

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      This study aimed at identifying intracellular stores which release Zn2+ when pHi drops from 6.6 to 6.1. It was found that these stores are not mitochondria or acidic organelles, but rather intracellular Zn2+ ligands. When the pH was decreasing from 6.6 to 6.1, only zinc–cysteine complexes showed a rapid acceleration in the rate of Zn2+ release. Therefore, the stores responsible for an acid-induced intracellular Zn2+ release in neurons may be the cytosolic zinc–cysteine complexes.

  11. Reviews

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      Macrophages and CNS remyelination

      Veronique E. Miron and Robin J. M. Franklin

      Article first published online: 26 MAR 2014 | DOI: 10.1111/jnc.12705

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      Here, we review the roles of microglia, monocytes and the macrophages, which they give rise to in creating lesion environments favourable to remyelination, highlighting the specific roles of activation phenotypes and how the pro-regenerative role of the innate immune system is altered by ageing.

  12. Original Articles

    1. 2,3,7,8-Tetrachlorodibenzo-p-dioxin promotes astrocyte activation and the secretion of tumor necrosis factor-α via PKC/SSeCKS-dependent mechanisms

      Yang Zhang, Xiaoke Nie, Tao Tao, Wenbo Qian, Shengyang Jiang, Junkang Jiang, Aihong Li, Aisong Guo, Guangfei Xu and Qiyun Wu

      Article first published online: 24 MAR 2014 | DOI: 10.1111/jnc.12696

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      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits neurotoxic effects. Here, we show TCDD induces pro-inflammatory responses in astrocytes. TCDD initiates an increase of [Ca2+]i, followed by the activation of PKC, which then induces the activation of Src-suppressed C-kinase substrate (SSeCKS). SSeCKS promotes NF-κB activation and the secretion of TNF-α and nitric oxide in astrocytes.

    2. CDK5 protects from caspase-induced Ataxin-3 cleavage and neurodegeneration

      Jan Liman, Sebastian Deeg, Aaron Voigt, Hannes Voßfeldt, Christoph P. Dohm, André Karch, Jochen Weishaupt, Jörg B. Schulz, Mathias Bähr and Pawel Kermer

      Article first published online: 24 MAR 2014 | DOI: 10.1111/jnc.12684

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      We propose that increased caspase-dependent cleavage of mutated Ataxin-3, because of missing CDK5 shielding, leads to aggregation and cell death. Moreover, reduction of CDK5 expression levels by RNAi in vivo enhances SCA3 toxicity as assayed in a Drosophila model for SCA3. We think that CDK5 functions as a shield against cleavage-induced toxification and thereby is an interesting target for therapeutic intervention in polyQ disease in general.

    3. You have full text access to this OnlineOpen article
      Altered brain protein expression profiles are associated with molecular neurological dysfunction in the PKU mouse model

      Esther Imperlini, Stefania Orrù, Claudia Corbo, Aurora Daniele and Francesco Salvatore

      Article first published online: 24 MAR 2014 | DOI: 10.1111/jnc.12683

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      We identified a set of proteins whose expression is affected by hyperphenylalaninemia. We think that phenylketonuria (PKU) brain dysfunction also depends on reduced Syn2 and Dpysl2 levels, increased Glu2/3 and NR1 levels, and decreased Pkm, Ckb, Pgam1 and Eno1 levels. These findings finally confirm that alteration in synaptic function, in transmission and in energy metabolism underlie brain damage provoked by hyperphenylalaninemias.

    4. Guanosine protects C6 astroglial cells against azide-induced oxidative damage: a putative role of heme oxygenase 1

      André Quincozes-Santos, Larissa Daniele Bobermin, Débora Guerini Souza, Bruna Bellaver, Carlos-Alberto Gonçalves and Diogo Onofre Souza

      Article first published online: 24 MAR 2014 | DOI: 10.1111/jnc.12694

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      Guanosine protects against azide-induced oxidative damage in C6 astroglial cells. Azide-induced mitochondrial dysfunction (1); increased reactive oxygen species/reactive nitrogen species levels (2); decreased glutamate uptake (3), GS activity (4), GSH levels (5), and SOD (6) and CAT (7) activities; increased glutathione peroxidase (GPx) (8) and NADPH oxidase (9) activities and cellular superoxide levels (10); increased NF-κB activation (11), TNF-α and IL-1β levels (12); and induced iNOS expression (13). Guanosine prevented these effects through the HO1 signaling pathway, thus our findings support the antioxidant effects of guanosine.

  13. Editorial Highlights

    1. You have free access to this content
      LRRK2: dropping (kinase) inhibitions and seeking an (immune) response

      Adamantios Mamais and Mark R. Cookson

      Article first published online: 24 MAR 2014 | DOI: 10.1111/jnc.12691

      Read the full articleInterferon-γinduces leucine-rich repeat kinase LRRK2 via extracellular signal-regulated kinase ERK5 in macrophages’ on doi: 10.1111/jnc.12668

  14. Original Articles

    1. A new semisynthetic derivative of sauroine induces LTP in hippocampal slices and improves learning performance in the Morris Water Maze

      Mariana Vallejo, Sebastián Loyola, Darwin Contreras, Gonzalo Ugarte, Diego Cifuente, Gabriela Ortega, José L. Cabrera, Marc Zeise, Carlos Tonn, Mario Carreño, Ricardo Delgado, Bernardo Morales and Mariel Agnese

      Article first published online: 24 MAR 2014 | DOI: 10.1111/jnc.12685

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      A semisynthetic derivative of sauroine, diacetyl sauroine (DAS), induces chemical long-term potentiation in rat hippocampal slices increasing the NMDA receptor-dependent current. 2 mg/kg prior to each session in a Morris Water Maze (MWM) improves behavior performance. In slices prepared from the tested rats the electrical stimulation-dependent long-term potentiation (LTP) was greatly enhanced. Therefore, DAS may have potency as a nootropic drug against the memory decline.

    2. Divergent developmental expression and function of the proton-coupled oligopeptide transporters PepT2 and PhT1 in regional brain slices of mouse and rat

      Yongjun Hu, Yehua Xie, Richard F. Keep and David E. Smith

      Article first published online: 20 MAR 2014 | DOI: 10.1111/jnc.12687

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      Developmental gene and protein expression of peptide transporters was evaluated in various regions of rodent brain, along with age-dependent uptake of dipeptide. We found marked changes in protein expression and functional activity of PhT1 and PepT2, the former predominating in adult and the latter in neonate. These developmental changes may markedly impact the neural activity of endogenous and exogenous peptides/mimetics.

  15. Reviews

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      Animal models of sports-related head injury: bridging the gap between pre-clinical research and clinical reality

      Mariana Angoa-Pérez, Michael J. Kane, Denise I. Briggs, Nieves Herrera-Mundo, David C. Viano and Donald M. Kuhn

      Article first published online: 19 MAR 2014 | DOI: 10.1111/jnc.12690

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      Sports-related head injury (SRHI) has emerged as a significant public health issue as athletes can develop psychiatric and neurodegenerative disorders later in life. Animal models have always been an integral part of the study of human TBI but few existing methods are valid for studying SRHI. In this review, we propose criteria for effective animal models of SRHI. Movement of the head upon impact is judged to be of primary importance in leading to concussion and persistent CNS dysfunction.

  16. Original Articles

    1. Choline-mediated modulation of hippocampal sharp wave–ripple complexes in vitro

      Viktoria Fischer, Martin Both, Andreas Draguhn and Alexei V. Egorov

      Article first published online: 19 MAR 2014 | DOI: 10.1111/jnc.12693

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      In this study we asked whether choline, the precursor and degradation product of acetylcholine, directly affects hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave–ripple complexes (SPW-R). In addition, choline reduces synaptic transmission between hippocampal subfields. These effects are mediated by direct activation of muscarinic as well as nicotinic cholinergic pathways. Together, choline turns out to be a potent regulator of patterned activity within hippocampal networks.

    2. Inhibition of Rho-kinase protects cerebral barrier from ischaemia-evoked injury through modulations of endothelial cell oxidative stress and tight junctions

      Claire L. Gibson, Kirtiman Srivastava, Nikola Sprigg, Philip M. W. Bath and Ulvi Bayraktutan

      Article first published online: 18 MAR 2014 | DOI: 10.1111/jnc.12681

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      Inhibition of Rho-kinase (ROCK) activity in a mouse model of human ischaemic stroke significantly improved functional outcome while reducing cerebral lesion and oedema volumes compared to vehicle-treated counterparts. Studies conducted with brain microvascular endothelial cells exposed to OGD ± R in the presence of Y-27632 revealed restoration of intercellular junctions and suppression of prooxidant NADPH oxidase activity as important factors in ROCK inhibition-mediated BBB protection.

  17. Reviews

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      Protective and toxic roles of dopamine in Parkinson's disease

      Juan Segura-Aguilar, Irmgard Paris, Patricia Muñoz, Emanuele Ferrari, Luigi Zecca and Fabio A. Zucca

      Article first published online: 18 MAR 2014 | DOI: 10.1111/jnc.12686

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      Dopamine oxidation to dopamine o-quinone, aminochrome and 5,6-indolequinone plays an important role in neurodegeneration in Parkinson's disease since they induce mitochondria and protein degradation dysfunction; formation of neurotoxic alpha synuclein protofibrils and oxidative stress. However, the cells have a protective system against dopamine oxidation composed by dopamine uptake mediated by Vesicular monoaminergic transporter-2 (VMAT-2), neuromelanin formation, two-electron reduction and GSH-conjugation mediated by Glutathione S-transferase M2-2 (GSTM2).

  18. Original Articles

    1. Dopamine denervation of the prefrontal cortex increases expression of the astrocytic glutamate transporter GLT-1

      Peter J. Vollbrecht, Linda D. Simmler, Randy D. Blakely and Ariel Y. Deutch

      Article first published online: 18 MAR 2014 | DOI: 10.1111/jnc.12697

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      The glutamate transporter GLT-1 is expressed by astrocytes, which also express dopamine receptors. Regulation of prefrontal cortical (PFC) GLT-1 potentially offers a novel treatment approach to the cognitive deficits of schizophrenia. Partial PFC dopamine deafferentation increased membrane expression of GLT-1 protein and glutamate uptake, but did not alter levels of the other two neocortical glutamate transporters, GLAST and EAAC1.

    2. Interferon regulatory factor 8 protects against cerebral ischaemic-reperfusion injury

      Mei Xiang, Lang Wang, Sen Guo, Yan-Yun Lu, Hao Lei, Ding-Sheng Jiang, Yan Zhang, Yi Liu, Yan Zhou, Xiao-Dong Zhang and Hongliang Li

      Article first published online: 13 MAR 2014 | DOI: 10.1111/jnc.12682

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      In the present study, we found that the transcriptional factor IRF8 plays a protective role in the cerebral ischaemic-reperfusion injury by attenuating neuronal apoptosis, oxidative stress and inflammation. Besides the known function of IRF8 in regulating the inflammatory gene expression, we first demonstrated that IRF8 can directly modulate apoptosis and oxidative stress by controlling the relative genes expression.

    3. The Aβ-clearance protein transthyretin, like neprilysin, is epigenetically regulated by the amyloid precursor protein intracellular domain

      Caroline Kerridge, Nikolai D. Belyaev, Natalia N. Nalivaeva and Anthony J. Turner

      Article first published online: 12 MAR 2014 | DOI: 10.1111/jnc.12680

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      Amyloid precursor protein (APP) intracellular domain (AICD) regulates expression of the amyloid (Aβ)-degrading enzyme neprilysin (NEP). The Aβ-clearance protein transthyretin (TTR) is also epigenetically regulated by AICD, derived specifically from the neuronal APP695 isoform. Cell treatment with agents up-regulating ‘functional’ AICD increases production of TTR and NEP and reduces Aβ levels which might represent a viable therapeutic target in Alzheimer's disease.

  19. Reviews

    1. You have full text access to this OnlineOpen article
      Insights into the physiological function of the β-amyloid precursor protein: beyond Alzheimer's disease

      Edgar Dawkins and David H. Small

      Article first published online: 7 MAR 2014 | DOI: 10.1111/jnc.12675

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      This article reviews studies on the structure, expression and post-translational processing of β-amyloid precursor protein (APP), as well as studies on the effects of APP in vitro and in vivo. We conclude that the published data provide strong evidence that APP has a trophic function. APP is likely to be involved in neural stem cell development, neuronal survival, neurite outgrowth and neurorepair. However, the mechanisms by which APP exerts its actions remain to be elucidated. The available evidence suggests that APP interacts both intracellularly and extracellularly to regulate various signal transduction mechanisms.

    2. You have free access to this content
      Impaired one carbon metabolism and DNA methylation in alcohol toxicity

      Inna I. Kruman and Anna-Kate Fowler

      Article first published online: 7 MAR 2014 | DOI: 10.1111/jnc.12677

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      In this review, we summarize the role of one-carbon metabolism (OCM) aberrations in chronic alcohol-induced toxicity. OCM is a major donor of methyl groups for methylation reactions, particularly DNA methylation critical for epigenetic regulation of gene expression. Alcohol interference with OCM and consequent reduced availability of methyl groups, improper DNA methylation, and aberrant gene expression can play a causative role in alcohol toxicity.

  20. Original Articles

    1. Amyloid-β concentration and structure influences the transport and immunomodulatory effects of IVIG

      Diane M. Wuest and Kelvin H. Lee

      Article first published online: 6 MAR 2014 | DOI: 10.1111/jnc.12678

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      The mechanisms of action and transport across the blood–brain barrier (BBB) for an Alzheimer's disease therapeutic, intravenous immunoglobulin (IVIG), remain unknown. We investigated the transport of IVIG across endothelial cell BBB monolayers pre-incubated with amyloid-β peptides. We found that the concentration and structure of amyloid-β plays an important role in the effect of IVIG on BBB tightening and cytokine neutralization. (Note: Figure not drawn to scale.)

    2. Inhibition of glucosylceramide synthase stimulates autophagy flux in neurons

      Wei Shen, Anastasia G. Henry, Katrina L. Paumier, Li Li, Kewa Mou, John Dunlop, Zdenek Berger and Warren D. Hirst

      Article first published online: 3 MAR 2014 | DOI: 10.1111/jnc.12672

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      Inhibition of GlcCer synthase enhances autophagy by inhibiting AKT-mTOR signaling, and increases the number and size of lysosomal/late endosomal structures. Furthermore, inhibition of GlcCer synthase decreased levels of mutant α-synuclein in neurons, which may represent a potential therapeutic target for Parkinson's disease.

    3. In vivo brain macromolecule signals in healthy and glioblastoma mouse models: 1H magnetic resonance spectroscopy, post-processing and metabolite quantification at 14.1 T

      Mélanie Craveiro, Virginie Clément-Schatlo, Denis Marino, Rolf Gruetter and Cristina Cudalbu

      Article first published online: 26 FEB 2014 | DOI: 10.1111/jnc.12673

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      In 1H magnetic resonance spectroscopy, the precise knowledge of the macromolecule signals is essential. After introducing a novel method for a flexible and robust post-processing of measured macromolecule signals, the absence of significant differences in metabolite quantification as a result of regional macromolecule variability was demonstrated in the mouse brain while several alterations of the macromolecule spectrum were observed in a mouse model of human glioma.

    4. Interferon-γ induces leucine-rich repeat kinase LRRK2 via extracellular signal-regulated kinase ERK5 in macrophages

      Martin Kuss, Eleni Adamopoulou and Philipp J. Kahle

      Article first published online: 24 FEB 2014 | DOI: 10.1111/jnc.12668

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      Leucine-rich repeat kinase 2 (LRRK2) is a major risk factor for the development of Parkinson's disease (PD). However, the role of LRRK2 in the affected neurons remains enigmatic. Recently, LRRK2 has been reported to be strongly expressed in the immune system. Here, we demonstrate that LRRK2 is induced by Interferon gamma via extracellular signal-regulated kinase 5 (ERK5) in macrophages, thus providing new insights in LRRK2 and ERK5 biology.

    5. Targeted gene mutation of E2F1 evokes age-dependent synaptic disruption and behavioral deficits

      Jenhao H. Ting, David R. Marks, Stephanie S. Schleidt, Joanna N. Wu, Jacob W. Zyskind, Kathryn A. Lindl, Julie A. Blendy, R. Christopher Pierce and Kelly L. Jordan-Sciutto

      Article first published online: 12 FEB 2014 | DOI: 10.1111/jnc.12655

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      E2F1 is a transcription factor regulating cell cycle progression and apoptosis. Although E2F1 dysregulation under toxic conditions can lead to neuronal death, little is known about its physiologic activity in the healthy brain. Here, we report significant age-dependent olfactory and memory deficits in mice with dysfunctional E2F1. Coincident with these behavioral changes, we also found age-matched synaptic disruption and persisting reduction in adult neurogenesis. Our study demonstrates that E2F1 contributes to physiologic brain structure and function.

    6. Effects of a novel orally administered calpain inhibitor SNJ-1945 on immunomodulation and neurodegeneration in a murine model of multiple sclerosis

      Nicole Trager, Amena Smith, Gerald Wallace IV, Mitsuyoshi Azuma, Jun Inoue, Craig Beeson, Azizul Haque and Naren L. Banik

      Article first published online: 12 FEB 2014 | DOI: 10.1111/jnc.12659

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      Multiple sclerosis (MS) pathology is marked by inflammation and infiltration of myelin-specific T cells into the central nervous system. Inflammation leads to neurodegeneration in progressive MS which also leads to epitope spreading, feedback looping to more inflammation. Calpain can play a role in both arms of the disease. Here, oral dosing with SNJ-1945, a novel water-soluble calpain inhibitor, reduces experimental autoimmune encephalomyelitis clinical scores in vivo and has a two-pronged effect via anti-inflammation and protection against neurodegeneration.

    7. Serum miR-206 and other muscle-specific microRNAs as non-invasive biomarkers for Duchenne muscular dystrophy

      Jun Hu, Min Kong, Yuanzhen Ye, Siqi Hong, Li Cheng and Li Jiang

      Article first published online: 12 FEB 2014 | DOI: 10.1111/jnc.12662

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      There has been a long-standing need for reliable, non-invasive biomarkers for Duchenne muscular dystrophy (DMD). We found that the levels of muscle-specific microRNAs, especially miR-206, in the serum of DMD were 2- to 4-fold higher than in the controls. High levels corresponded to low muscle strength, muscle function, and quality of life (QoL). These miRNAs were able to discriminate DMD from controls by receiver operating characteristic (ROC) curves analyses. Thus, miR-206 and other muscle-specific miRNAs are useful as non-invasive biomarkers for DMD.

    8. Profiling the genes affected by pathogenic TDP-43 in astrocytes

      Cao Huang, Bo Huang, Fangfang Bi, Linda H Yan, Jianbin Tong, Jufang Huang, Xu-Gang Xia and Hongxia Zhou

      Article first published online: 9 FEB 2014 | DOI: 10.1111/jnc.12660

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      Restricted expression of pathogenic TDP-43 in astrocytes causes non-cell-autonomous motor neuron death in transgenic rats. As revealed by microarray assay, pathogenic TDP-43 in astrocytes preferentially altered expression of the genes encoding secretory proteins. Whereas neurotrophic genes were down-regulated, neurotoxic genes were up-regulated. Therefore, TDP-43 pathogenesis is associated with simultaneous induction of neurotoxic genes and repression of neurotrophic genes in astrocytes.

    9. You have full text access to this OnlineOpen article
      Botulinum protease-cleaved SNARE fragments induce cytotoxicity in neuroblastoma cells

      Jason Arsenault, Sabine A. G. Cuijpers, Enrico Ferrari, Dhevahi Niranjan, Aleksander Rust, Charlotte Leese, John A. O'Brien, Thomas Binz and Bazbek Davletov

      Article first published online: 23 JAN 2014 | DOI: 10.1111/jnc.12645

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      Ternary complex formation by synaptobrevin (green) and syntaxin/synaptosomal-associated protein of 25 kDa (red) is necessary for vesicle fusion, membrane trafficking, and cell homeostasis. Botulinum proteases cleave the three SNAREs proteins as indicated, resulting in a loss of cell viability. Lipofection reagents were used to deliver botulinum proteases or short SNARE peptides into neuroblastoma cells, revealing cytotoxic effects of SNARE fragments.

    10. SNJ-1945, a calpain inhibitor, protects SH-SY5Y cells against MPP+ and rotenone

      Varduhi H. Knaryan, Supriti Samantaray, Sookyoung Park, Mitsuyoshi Azuma, Jun Inoue and Naren L. Banik

      Article first published online: 16 DEC 2013 | DOI: 10.1111/jnc.12629

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      SH-SY5Y cells, differentiated as dopaminergic (TH positive) and cholinergic (ChAT positive), were used as in vitro models for Parkinson's disease. MPP+ and rotenone induced up-regulation of calpain, expression, and activity as a common mechanism of neurodegeneration. SNJ-1945, a novel calpain inhibitor, protected both the cell phenotypes against MPP+ and rotenone.

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