Journal of Neurochemistry

Cover image for Vol. 133 Issue 1

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 - 63
  1. Original Articles

    1. Neuroprotective effects of vildagliptin in rat rotenone Parkinson's disease model: role of RAGE-NFκB and Nrf2-antioxidant signaling pathways

      Rania M. Abdelsalam and Marwa M. Safar

      Article first published online: 26 MAR 2015 | DOI: 10.1111/jnc.13087

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      In the rat rotenone model of Parkinson's disease (PD), striatal RAGE/NFκB signaling was up-regulated associated with elevated levels of inflammatory, oxidative stress, and apoptotic mediators resulting in dopaminergic neurons death and hence motor impairment. Vildagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, blocked the RAGE/NFκB cascade exerting a potential antiparkinsonian effect. RAGE, receptor for advanced glycation end product; NFκB, nuclear factor κB; TNFα, tumor necrosis factor alpha; ICAM, intracellular adhesion molecule; iNOS, inducible nitric oxide synthase; MPO, myeloperoxidase.

    2. The intracellular domain of L1CAM binds to casein kinase 2α and is neuroprotective via inhibition of the tumor suppressors PTEN and p53

      Yan Wang and Melitta Schachner

      Article first published online: 25 MAR 2015 | DOI: 10.1111/jnc.13083

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      L1CAM (L1 cell adhesion molecule) is implicated in neural functions through the cognate src/MAP kinase signaling pathway. We now describe a novel signaling platform operating via the alpha subunit of casein kinase 2 which binds to the intracellular domain of L1. Knockdown of L1CAM leads to increased levels of tumor suppressor PTEN (phosphatase and tensin homolog) and p53, known to inhibit neuritogenesis in vitro and recovery from trauma in vivo. By activating this enzyme, L1CAM adds to its beneficial functions by decreasing the levels of PTEN and p53.

    3. Receptive range analysis of a mouse odorant receptor subfamily

      Jingyi Li, Rafi Haddad, Vanessa Santos, Selvan Bavan and Charles W. Luetje

      Article first published online: 25 MAR 2015 | DOI: 10.1111/jnc.13095

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      We screened a small group of mouse odorant receptors (MORs) with a diverse odorant panel to identify a new odorant-OR pairing (unsaturated aldehydes and MOR263-3), then extensively screened a series of additional MORs related to MOR263-3 in various ways. MORs related by phylogenetic analysis had odorant specificities that overlapped with that of MOR263-3, but MOR171-17, predicted to be functionally related to MOR263-3 by an alternative bioinformatic analysis, had a distinct odorant specificity.

    4. Estrogen-related receptor gamma regulates dopaminergic neuronal phenotype by activating GSK3β/NFAT signaling in SH-SY5Y cells

      Juhee Lim, Hueng-Sik Choi and Hyun Jin Choi

      Article first published online: 25 MAR 2015 | DOI: 10.1111/jnc.13085

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      We propose the relevance of estrogen-related receptor gamma (ERRγ) in regulating dopaminergic neuronal phenotype: ERRγ is up-regulated by retinoic acid in SH-SY5Y cells, and enhances dopaminergic phenotypes and induces neurite outgrowth; Polo-like kinase 2 (PLK2) and glycogen synthase kinase 3 beta/nuclear factor of activated T cells (GSK3β/NFAT) signaling are responsible for the ERRγ effect. Our findings provide the first insights into the role of ERRγ in the brain, as a novel approach toward understanding dopaminergic differentiation.

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      Corticosterone primes the neuroinflammatory response to DFP in mice: potential animal model of Gulf War Illness

      James P. O'Callaghan, Kimberly A. Kelly, Alicia R. Locker, Diane B. Miller and Steve M. Lasley

      Article first published online: 24 MAR 2015 | DOI: 10.1111/jnc.13088

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      Gulf War (GW) veterans were exposed to stressors, prophylactic medicines and, potentially, nerve agents in theater. Subsequent development of GW Illness, a persistent multi-symptom disorder with features characteristic of sickness behavior, may be caused by priming of the CNS resulting in exaggerated neuroinflammatory responses to pathogens/insults. Nerve agent, diisopropyl fluorophosphate (DFP), produced a neuroinflammatory response that was exacerbated by pre-treatment with levels of corticosterone simulating heightened stressor conditions. While prophylactic treatments reduced DFP-induced neuroinflammation, this effect was negated when those treatments were combined with corticosterone.

    6. You have full text access to this OnlineOpen article
      Expression of the synaptic exocytosis-regulating molecule complexin 2 in taste buds and its participation in peripheral taste transduction

      Azusa Kurokawa, Masataka Narukawa, Makoto Ohmoto, Joto Yoshimoto, Keiko Abe and Takumi Misaka

      Article first published online: 23 MAR 2015 | DOI: 10.1111/jnc.13073

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      A part of taste information is thought to be transmitted via synapses. However, the molecular mechanisms have not been fully elucidated. To identify molecules that participate in synaptic taste transduction, we investigated complexins (Cplxs) expression in taste bud cells. Strong expression of Cplx2 mRNA was detected in taste bud cells. Furthermore, taste responses to some sour stimuli in CPLX2- knockout mice were significantly lower than those in wild-type mice. These suggested that CPLX2 participated in synaptic taste transduction.

    7. Characterization of traumatic brain injury in human brains reveals distinct cellular and molecular changes in contusion and pericontusion

      Gangadharappa Harish, Anita Mahadevan, Nupur Pruthi, Sreelakshmi K. Sreenivasamurthy, Vinuth N. Puttamallesh, Thottethodi Subrahmanya Keshava Prasad, Susarla Krishna Shankar and Muchukunte Mukunda Srinivas Bharath

      Article first published online: 20 MAR 2015 | DOI: 10.1111/jnc.13082

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      We have characterized the primary injury in human traumatic brain injury (TBI). Contusions (Ct) – the injury core displayed hemorrhages, inflammation, and astrogliosis, while the surrounding pericontusion (PC) revealed edema, vacuolation, microglial activation, axonal loss, and dystrophy. Proteomic analysis demonstrated altered immune response, synaptic and mitochondrial dysfunction in Ct, and altered regulation of neurogenesis and cytoskeletal architecture in PC. Ct displayed more oxidative damage, mitochondrial, and synaptic dysfunction compared to PC.

    8. Recombinant adeno-associated viral (rAAV) vectors mediate efficient gene transduction in cultured neonatal and adult microglia

      Wei Su, John Kang, Bryce Sopher, James Gillespie, Macarena S. Aloi, Guy L. Odom, Stephanie Hopkins, Amanda Case, David B. Wang, Jeffrey S. Chamberlain and Gwenn A. Garden

      Article first published online: 20 MAR 2015 | DOI: 10.1111/jnc.13081

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      Neonatal microglia are functionally distinct from adult microglia, although the majority of in vitro studies utilize rodent neonatal microglia cultures because of difficulties of culturing adult cells. In addition, cultured microglia are refractory to most methods for modifying gene expression. Here, we developed a novel protocol for culturing adult microglia and evaluated the feasibility and efficiency of utilizing Recombinant Adeno-Associated Virus (rAAV) to modulate gene expression in cultured microglia.

    9. Amyloid β-abrogated TrkA ubiquitination in PC12 cells analogous to Alzheimer's disease

      Chen Zheng, Thangiah Geetha, Marla Gearing and Jeganathan Ramesh Babu

      Article first published online: 19 MAR 2015 | DOI: 10.1111/jnc.13076

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      Cell survival and differentiation are essential for living organisms. We propose that under normal conditions, nerve growth factor (NGF) leads to Tropomyosin receptor kinase A (TrkA) phosphorylation, ubiquitination and its association with p75NTR, p62 and TRAF6, thereby promoting cell survival and differentiation. In diseased conditions such as Alzheimer's, proNGF leads to nitrotyrosylation of TrkA, thereby impairing its ubiquitination and downstream signaling which results in apoptosis. TRAF6 = tumor necrosis factor receptor-associated factor 6; Ub = ubiquitin.

    10. Functional characterization of mutants in the transmembrane domains of the rat P2X7 receptor that regulate pore conductivity and agonist sensitivity

      Marie Jindrichova, Anirban Bhattacharya, Marian Rupert, Petr Skopek, Tomas Obsil and Hana Zemkova

      Article first published online: 18 MAR 2015 | DOI: 10.1111/jnc.13078

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      We investigated the mechanism of the proapoptotic receptor P2X7R's large pore opening and its sensitization. We found that aromatic residues in the upper part of the first transmembrane domain (TM1) are critical for both the P2X7R channel pore opening and receptor sensitization, and residues located at or below the intersection of the second transmembrane domains (TM2) control the rate of pore opening. These findings identify new residues involved in pore formation of P2X7R.

  2. Reviews

    1. You have full text access to this OnlineOpen article
      APOE-modulated Aβ-induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective

      Leon M. Tai, Shivesh Ghura, Kevin P. Koster, Vaiva Liakaite, Mark Maienschein-Cline, Pinal Kanabar, Nicole Collins, Manel Ben-Aissa, Arden Zhengdeng Lei, Neil Bahroos, Stefan J. Green, Bill Hendrickson, Linda J. Van Eldik and Mary Jo LaDu

      Article first published online: 18 MAR 2015 | DOI: 10.1111/jnc.13072

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      In this editorial review, we present data supporting the hypothesis that impaired apoE4 function modulates Aβ-induced effects on inflammatory receptor signaling, including amplification of detrimental (TLR4-p38α) and suppression of beneficial (IL-4R-nuclear receptor) pathways, resulting in an adverse NIP that causes neuronal dysfunction. NIP, Neuroinflammatory phenotype; P.I., pro-inflammatory; A.I., anti-inflammatory.

  3. Original Articles

    1. Brain area-specific diurnal and photic regulation of val-opsinA and val-opsinB genes in the zebrafish

      Chong Yee Hang, Takashi Kitahashi and Ishwar S. Parhar

      Article first published online: 17 MAR 2015 | DOI: 10.1111/jnc.13084

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      We show diurnal expression changes of vertebrate ancient long (VAL) opsin genes (valopa and valopb), depending on brain area, time of day and light condition, in the adult male zebrafish. Differential regulation of the valop genes in the thalamus and arrhythmic expression in the midbrain and hindbrain suggest their involvement in time- and light-dependent physiology to adjust to environmental changes.

    2. Prion protein regulates glutathione metabolism and neural glutamate and cysteine uptake via excitatory amino acid transporter 3

      Kathrin Guitart, Gabriele Loers, Melitta Schachner and Ralf Kleene

      Article first published online: 17 MAR 2015 | DOI: 10.1111/jnc.13071

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      Interactions of prion protein (PrP) with excitatory amino acid transporter 3 (EAAT3), γ-glutamyl transpeptidase (GGT) and multi-drug resistance protein 1 (MRP1) regulate the astroglial and neuronal metabolism of glutathione (GSH) which protects cells against the cytotoxic oxidative stress. PrP controls the release of GSH from astrocytes via MRP1 and regulates the hydrolysis of extracellular GSH by GGT as well as the neuronal and astroglial glutamate and cysteine uptake via EAAT3.

  4. Editorial Highlights

    1. You have free access to this content
      Cooperativity between individual transporter protomers: new data fuelling old complexes

      Harald H. Sitte, Gerhard J. Schütz and Michael Freissmuth

      Article first published online: 15 MAR 2015 | DOI: 10.1111/jnc.13086

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      Neurotransmitter transporters are arranged in an oligomeric quaternary structure as evidenced by crosslinking or fluorescence resonance energy transfer (FRET)-microscopy. In a study by Zhen and colleagues highlighted by this Editorial in the current issue of Journal of Neurochemistry, the combination of mutant and wild-type dopamine transporter (DAT) has been used to establish the cooperation between transporter protomers; the DAT mutant version has an altered affinity for the radiolabelled inhibitor [3H]CFT. Zhen and colleagues predict how saturation-binding curves ought to look, if the two binding sites (i.e. of the wild type and the mutant DAT) operated independently. The results are clear-cut: the experimental observations are inconsistent with curves obtained by mixing independent binding sites. Thus, by definition, the binding sites cooperate.

      Read the full article ‘Dopamine transporter oligomerization: impact of combining protomers with differential cocaine analog binding affinities’ on page doi: 10.1111/jnc.13025.

  5. Original Articles

    1. Dysregulation of inter-photoreceptor retinoid-binding protein (IRBP) after induced Müller cell disruption

      Ling Zhu, Weiyong Shen, Brian Lyons, Ying Wang, Fanfan Zhou and Mark C. Gillies

      Article first published online: 15 MAR 2015 | DOI: 10.1111/jnc.13075

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      This study reports down-regulation of inter-photoreceptor retinoid-binding protein (IRBP) in photoreceptors and retinoid cycle derangement after Müller cell disruption in a transgenic mouse model. The findings indicate that Müller cells communicate with photoreceptors in response to stress by secreting soluble protein factor(s). We propose that down-regulation of IRBP may represent an early and novel pathogenic mechanism in degenerative retinal diseases.

    2. Targeting cyclin D3/CDK6 activity for treatment of Parkinson's disease

      Carolina Alquézar, Estíbaliz Barrio, Noemí Esteras, Ana de la Encarnación, Fernando Bartolomé, José A. Molina and Ángeles Martín-Requero

      Article first published online: 15 MAR 2015 | DOI: 10.1111/jnc.13070

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      We report here that peripheral cells from Parkinson's disease (PD) patients show an enhanced proliferative activity due to the activation of cyclin D3/CDK6-mediated phosphorylation of retinoblastoma protein (pRb). Treatment of PD lymphoblasts with inhibitors of histone deacetylases like suberoylanilide hydroxamic acid (SAHA) and sodium butyrate (NaB), or with rapamycin, inhibitor of mechanistic target of rapamycin (mTOR) normalized the proliferation of PD lymphoblasts by preventing the over-activation of the cyclin D3/CDK6/pRb cascade. These drugs were shown to have neuroprotective effects in both human neuroblastoma SH-SY5Y cells and primary rat mid-brain dopaminergic neuronal cultures toxicity induced by 6-hidroxydopamine. Considering that these drugs are already used in clinic for treatment of other diseases with good tolerance, it seems reasonable to believe that the repositioning of these drugs toward PD holds promise as a novel therapeutic strategy.

    3. Uptake and metabolism of fructose by rat neocortical cells in vivo and by isolated nerve terminals in vitro

      Bjørnar Hassel, Ahmed Elsais, Anne-Sofie Frøland, Erik Taubøll, Leif Gjerstad, Yi Quan, Raymond Dingledine and Frode Rise

      Article first published online: 13 MAR 2015 | DOI: 10.1111/jnc.13079

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      We asked how the brain handles fructose, which may react spontaneously with proteins to form ‘advanced glycation end products’ and trigger inflammation. Neocortical cells took up and metabolized extracellular fructose oxidatively in vivo, and isolated nerve terminals did so in vitro. The low expression of fructose transporter Glut5 limited uptake of extracellular fructose. Hexokinase was a main pathway for fructose metabolism, but ketohexokinase (which leads to glyceraldehyde formation) was expressed too. Neocortical cells also took up and metabolized glyceraldehyde oxidatively.

    4. Ghrelin regulates phasic dopamine and nucleus accumbens signaling evoked by food-predictive stimuli

      Jackson J. Cone, Jamie D. Roitman and Mitchell F. Roitman

      Article first published online: 13 MAR 2015 | DOI: 10.1111/jnc.13080

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      Cues that predict food availability powerfully regulate food-seeking behavior. Here we show that cue-evoked changes in both nucleus accumbens (NAc) dopamine (DA) and NAc cell activity are modulated by intra-cranial infusions of the stomach hormone ghrelin - a hormone known to act centrally to promote food intake. These data demonstrate that hormones associated with physiological state (i.e., hunger) can affect encoding of food-predictive cues in brain regions that drive food-motivated behavior.

    5. Kinetic diversity of dopamine transmission in the dorsal striatum

      I. Mitch Taylor, Kathryn M. Nesbitt, Seth H. Walters, Erika L. Varner, Zhan Shu, Kathleen M. Bartlow, Andrea S. Jaquins-Gerstl and Adrian C. Michael

      Article first published online: 13 MAR 2015 | DOI: 10.1111/jnc.13059

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      The dorsal striatum is composed of five significantly different dopamine domains (types 1–4 and slow, average ± SEM responses to medial forebrain bundle (MFB) stimulation are shown in the figure). Responses from each of these five domains exhibit significantly different ascending and descending kinetic profiles and return to a long lasting elevated dopamine state, termed the dopamine hang-up. All features of these responses are modeled with high correlation using first-order modeling as well as our recently published restricted diffusion model of evoked dopamine overflow. We also report that functionally distinct subregions of the dorsal striatum express selective dopamine kinetic diversity.

    6. Ligand-directed delivery of fluorophores to track native calcium-permeable AMPA receptors in neuronal cultures

      Rosamund E. Combs-Bachmann, Jeffreys Nate Johnson, Devaiah Vytla, Amanda M. Hussey, Maria L. Kilfoil and James J. Chambers

      Article first published online: 13 MAR 2015 | DOI: 10.1111/jnc.13051

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      We used a small molecule, ligand-directed probe to deliver synthetic fluorophores to endogenously expressed glutamate receptors for the purpose of tracking these receptors on live, hippocampal neurons. We found that clusters of receptors appear to move at similar rates to previous studies. We also found that the polyamine toxin pharmacophore likely binds to receptors in addition to calcium-permeable AMPA receptors.

    7. Early growth response 1 (Egr-1) directly regulates GABAA receptor α2, α4, and θ subunits in the hippocampus

      Jiwon Mo, Chong-Hyun Kim, Dongmin Lee, Woong Sun, Hyun Woo Lee and Hyun Kim

      Article first published online: 11 MAR 2015 | DOI: 10.1111/jnc.13077

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      The early growth response 1 (Egr-1) is an inducible transcription factor to mediate rapid gene expression by neuronal activity. However, its underlying molecular target genes and mechanisms are not fully understood. We suggest that GABAA receptor subunits, GABRA2 (α2), GABRA4 (α4), and GABRQ (θ) genes are transcriptional targets of Egr-1. Neuronal activity-dependent up-regulation of Egr-1 might lead to altered subtypes of GABAA receptors for the maintenance of homeostatic excitatory and inhibitory balance for the regulation of synaptic strength.

    8. Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid

      Dongxian Zhang, Brian Lee, Anthony Nutter, Paul Song, Nima Dolatabadi, James Parker, Sara Sanz-Blasco, Traci Newmeyer, Rajesh Ambasudhan, Scott R. McKercher, Eliezer Masliah and Stuart A. Lipton

      Article first published online: 11 MAR 2015 | DOI: 10.1111/jnc.13074

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      Cyanide, a potential bioterrorist agent, can produce a chronic delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Here, cyanide poisoning treated with the proelectrophillic compound carnosic acid, results in reduced neuronal cell death in both in vitro and in vivo models through activation of the Nrf2/ARE transcriptional pathway. Carnosic acid is therefore a potential treatment for the toxic central nervous system (CNS) effects of cyanide poisoning. ARE, antioxidant responsive element; Nrf2 (NFE2L2, Nuclear factor (erythroid-derived 2)-like 2).

  6. Reviews

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      Microglia and neuroprotection

      Zhihong Chen and Bruce D. Trapp

      Article first published online: 10 MAR 2015 | DOI: 10.1111/jnc.13062

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      Microglia are the resident innate immune cells of the CNS. Despite the traditional view of microglia as being destructive in neurological diseases, recent studies have shown that they maintain tissue homeostasis and protect the CNS under various pathological conditions. They achieve so by clearing debris, promoting neurogenesis, suppressing inflammation and stripping inhibitory synapses. This review summarizes recent advances of our understanding on the multi-dimensional neuroprotective roles of microglia.

  7. Original Articles

    1. Different contributions of calcium channel subtypes to electrical excitability of chromaffin cells in rat adrenal slices

      Elisa Albiñana, Pedro Segura-Chama, Andres M. Baraibar, Arturo Hernández-Cruz and Jesus M. Hernández-Guijo

      Article first published online: 10 MAR 2015 | DOI: 10.1111/jnc.13055

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      This study demonstrates that Ca2+ influx through L-type Ca2+ channels plays a key role in modulating the threshold potential for action potential firing and activating BK channels contributing to repolarization and afterhyperpolarization from rat adrenal chromaffin cells in situ.

    2. Molecular mechanisms of non-transferrin-bound and transferring-bound iron uptake in primary hippocampal neurons

      Changyi Ji and Daniel J. Kosman

      Article first published online: 10 MAR 2015 | DOI: 10.1111/jnc.13040

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      Analysis of the expression and localization of known iron uptake transporters demonstrated that Zip8 makes a major contribution to iron accumulation in primary cultures of rat embryonic hippocampal neurons. These cells exhibit uptake pathways for ferrous and ferric iron (non-transferrin-bound iron, NTBI in figure) and for transferrin-bound iron; the ferrireductases Steap2 and SDR2 support the uptake of ferric iron substrates. Zip8 and Steap2 are strongly expressed in the plasma membrane of both soma and processes, implying a crucial role in iron accumulation from NTBI and transferrin-bound iron (TBI) by hippocampal neurons.

    3. APLP1 and APLP2, members of the APP family of proteins, behave similarly to APP in that they associate with NMDA receptors and enhance NMDA receptor surface expression

      Sarah L. Cousins, Wei Dai and F. Anne Stephenson

      Article first published online: 8 MAR 2015 | DOI: 10.1111/jnc.13063

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      Amyloid precursor protein (APP) has been shown to associate with N-methyl-d-aspartate (NMDA) receptors and to enhance their cell surface expression. Here, we show that the other members of the APP family, APLP1 and APLP2, behave similarly to APP in that they both associate with assembled NMDA receptors in the endoplasmic reticulum via their interaction with the NMDA receptor subunit, GluN1 and, they enhance receptor cell surface expression. Alternative scenarios are depicted since it is to be determined if respective associations are direct.

    4. Positive allosteric modulation of alpha-7 nicotinic receptors promotes cell death by inducing Ca2+ release from the endoplasmic reticulum

      María Guerra-Álvarez, Ana J. Moreno-Ortega, Elisa Navarro, José Carlos Fernández-Morales, Javier Egea, Manuela G. López and María F. Cano-Abad

      Article first published online: 6 MAR 2015 | DOI: 10.1111/jnc.13049

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      This study focuses on how the type II positive allosteric modulator PNU120596 (PAM II PNU12) affects intracellular Ca2+ signaling and cell viability. Using SH-SY5Y neuroblastoma cells overexpressing α7-nAChRs (α7-SH) and their control (C-SH), we find that PAM of α7-nAChRs with PNU120596: (i) increases inward calcium current (ICa) and cytosolic Ca2+ concentration ([Ca2+]cyt); (ii) releases Ca2+ from the ER ([Ca2+]ER) by a Ca2+-induced Ca2+ release mechanism; and (iv) reduces cell viability. These findings were corroborated in rat hippocampal organotypic cultures. [Ca2+]cyt, cytosolic Ca2+ concentration; [Ca2+]ER, endoplasmic reticulum Ca2+ concentration; α7 nAChR, α7 isoform of nicotinic acetylcholine receptors; α7-SH, SH-SY5Y stably overexpressing α7 nAChRs cells; C-SH, control SH-SY5Y cells; Nic, nicotine; PNU12, PNU120596.

    5. Heat shock protein responses to aging and proteotoxicity in the olfactory bulb

      Tyler S. Crum, Amanda M. Gleixner, Jessica M. Posimo, Daniel M. Mason, Matthew T. Broeren, Scott D. Heinemann, Peter Wipf, Jeffrey L. Brodsky and Rehana K. Leak

      Article first published online: 5 MAR 2015 | DOI: 10.1111/jnc.13041

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      The olfactory bulb is affected in the early phases of many age-related neurodegenerative disorders. Here, we described the impact of aging on multiple heat shock proteins (Hsps), such as Hsp70, in the female rat olfactory bulb in vivo. Using multiple proteasome and Hsp70 inhibitors (see schematic), we found that proteotoxicity elicited a compensatory increase in Hsp70 in primary olfactory bulb cells in vitro. Hsp70 then reduced the proteotoxic buildup of ubiquitinated proteins and robustly protected against cell death according to three independent viability assays. Thus, olfactory bulb neurons can mount impressive natural adaptations to proteotoxic injury, perhaps explaining why neurodegenerative disorders are so delayed in onset and so slow to progress.

    6. Neuroprotective role of Nrf2 for retinal ganglion cells in ischemia-reperfusion

      Zhenhua Xu, Hongkwan Cho, Matthew J. Hartsock, Katherine L. Mitchell, Junsong Gong, Lijuan Wu, Yanhong Wei, Shuang Wang, Rajesh K. Thimmulappa, Michael B. Sporn, Shyam Biswal, Derek S. Welsbie and Elia J. Duh

      Article first published online: 4 MAR 2015 | DOI: 10.1111/jnc.13064

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      Oxidative stress is thought to be an important mediator of retinal ganglion cell death in ischemia-reperfusion injury. We found that the transcription factor NF-E2-related factor 2 (Nrf2), a major regulator of oxidative stress, is an important endogenous neuroprotective molecule in retinal ganglion cells in ischemia-reperfusion, exerting a cell-autonomous protective effect.  The triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) reduces neurodegeneration following ischemia-reperfusion in an Nrf2-dependent fashion. This suggests that Nrf2-activating drugs including triterpenoids could be a therapeutic strategy for retinal neuroprotection.

    7. Regulation of RAGE splicing by hnRNP A1 and Tra2β-1 and its potential role in AD pathogenesis

      Xiao-Yan Liu, Hong-Lei Li, Jia-Bin Su, Fei-Hong Ding, Jing-Jing Zhao, Fang Chai, Yuan-Xin Li, Shi-Cao Cui, Feng-Yan Sun, Zhi-Ying Wu, Ping Xu and Xian-Hua Chen

      Article first published online: 2 MAR 2015 | DOI: 10.1111/jnc.13069

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      The receptor for advanced glycation end products (RAGE) gene expresses two major alternative splicing isoforms, membrane-bound RAGE (mRAGE) and secretory RAGE (esRAGE). Both isoforms play important roles in Alzheimer's disease (AD) pathogenesis. Mechanism for imbalanced expression of these two isoforms in AD brain remains elusive. We proposed here a hypothetic model to illustrate that impaired glucose metabolism in AD brain may increase the expression of splicing protein hnRNP A1 and reduce Tra2β-1, which cause the imbalanced expression of mRAGE and esRAGE.

    8. Schwann cells contribute to neurodegeneration in transthyretin amyloidosis

      Tatsufumi Murakami, Kazunori Sango, Kazuhiko Watabe, Naoko Niimi, Shizuka Takaku, Zhenghua Li, Ken-ichi Yamamura and Yoshihide Sunada

      Article first published online: 2 MAR 2015 | DOI: 10.1111/jnc.13068

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      We established a spontaneously immortalized Schwann cell line derived from familial amyloidotic polyneuropathy transgenic mice. Conditioned medium from the cells contained variant transthyretin (TTR), and inhibited neurite outgrowth of neurons. TTR aggregates were observed in the Schwann cells and satellite cells of aged mice. Proteasome inhibition induced TTR aggregates as aggresomes in the cultured cells. These results support the hypothesis that Schwann cells contribute to neurodegeneration in familial amyloidotic polyneuropathy (FAP).

    9. Dynamic increases in AMPA receptor phosphorylation in the rat hippocampus in response to amphetamine

      Li-Min Mao, Bing Xue, Dao-Zhong Jin and John Q. Wang

      Article first published online: 2 MAR 2015 | DOI: 10.1111/jnc.13067

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      Acute injection of amphetamine increased phosphorylation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunits at a protein kinase A (PKA)-sensitive site (S845) in the rat hippocampus. This increase was dose- and time-dependent and correlated with an increase in surface GluA1 expression. Thus, amphetamine can upregulate GluA1 phosphorylation and surface trafficking of GluA1 in hippocampal neurons in vivo.

    10. G protein-coupled estrogen receptor-mediated effects on cytosolic calcium and nanomechanics in brain microvascular endothelial cells

      Joseph B. Altmann, Guang Yan, Jeffrey F. Meeks, Mary E. Abood, Eugen Brailoiu and G. Cristina Brailoiu

      Article first published online: 2 MAR 2015 | DOI: 10.1111/jnc.13066

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      Activation of the G protein-coupled estrogen receptor (GPER) in rat brain microvascular endothelial cells (RBMVEC) increases [Ca2+]i by promoting Ca2+ influx. The increase in [Ca2+]i leads to membrane hyperpolarization, nitric oxide (NO) production, and to cytoskeletal changes and increased cell stiffness. Our results unravel the mechanisms underlying GPER-mediated effects in RBMVEC with implications for the effect of estrogen on cerebral microvasculature.

    11. Noise-induced cochlear F-actin depolymerization is mediated via ROCK2/p-ERM signaling

      Yu Han, Xianren Wang, Jun Chen and Su-Hua Sha

      Article first published online: 2 MAR 2015 | DOI: 10.1111/jnc.13061

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      We propose the following cascade following noise trauma leading to alteration of the F-actin arrangement in the outer hair cell cytoskeleton: Noise exposure reduces the levels of GTP-RhoA and subsequently diminishes levels of RhoA effector ROCK2 (Rho-associated kinase 2). Phosphorylation of ezrin-radixin-moesin (ERM) by ROCK2 normally allows ERM to cross-link actin filaments with the plasma membrane. Noise-decreased levels of ROCK results in reduction of phosphorylation of ERM that leads to depolymerization of actin filaments. Lysophosphatidic acid (LPA), an agonist of RhoA, binds to the G-protein-coupled receptor (GPCR) leading to activation of RhoA through Gα12/13 and RhoGEF. Administration of LPA rescues the noise-diminished F/G-actin ratio.

    12. Possible involvement of 15-deoxy-Δ12,14-prostaglandin J2 in the development of leptin resistance

      Toru Hosoi, Syu Matsuzaki, Tsuyoshi Miyahara, Kaori Shimizu, Yuki Hasegawa and Koichiro Ozawa

      Article first published online: 2 MAR 2015 | DOI: 10.1111/jnc.13057

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      Leptin resistance, an insensitivity to the actions of leptin, is involved in the development of obesity. Here, we found 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) may be involved in the development of leptin resistance. The present results suggest that the 15d-PGJ2 may be a novel factor for the development of leptin resistance in obesity. 15d-PGJ2, 15-Deoxy-Δ12,14-prostaglandin J2; STAT3, signal tranducer and activator of transcription 3.

    13. 3,4-Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine-induced damage to dopamine nerve endings: β-ketoamphetamine modulation of neurotoxicity by the dopamine transporter

      John H. Anneken, Mariana Angoa-Pérez and Donald M. Kuhn

      Article first published online: 2 MAR 2015 | DOI: 10.1111/jnc.13048

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      METH (a) enters DA nerve endings via the DAT, causes leakage of DA into the cytoplasm and then into the synapse via DAT-mediated reverse transport. Methylone (METHY) and mephedrone (MEPH; b), like METH, are substrates for the DAT but release DA from cytoplasmic pools selectively. When METH is combined with METHY or MEPH (c), DA efflux and neurotoxicity are enhanced. MDPV (d), which is a non-substrate blocker of the DAT, prevents METH uptake and efflux of DA. Therefore, bath salts that are substrates for the DAT and release DA (METHY, MEPH) accentuate METH neurotoxicity, whereas those that are non-substrate blockers of the DAT (MDPV) are neuroprotective.

    14. Quantitative expression proteomics and phosphoproteomics profile of brain from PINK1 knockout mice: insights into mechanisms of familial Parkinson's disease

      Judy C. Triplett, Zhaoshu Zhang, Rukhsana Sultana, Jian Cai, Jon B. Klein, Hansruedi Büeler and David Allan Butterfield

      Article first published online: 1 MAR 2015 | DOI: 10.1111/jnc.13039

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      Mutations in PINK1 are associated with an early-onset form of Parkinson's disease (PD). This study examines changes in the proteome and phosphoproteome of the PINK1 knockout mouse brain. Alterations were noted in several key proteins associated with: increased oxidative stress, aberrant cellular signaling, altered neuronal structure, decreased synaptic plasticity, reduced neurotransmission, diminished proteostasis networks, and altered metabolism. 14-3-3ε, 14-3-3 protein epsilon; 3-PGDH, phosphoglycerate dehydrogenase; ALDOA, aldolase A; APT1, acyl-protein thioesterase 1; CaM, calmodulin; CBR3, carbonyl reductase [NADPH] 3; ENO2, gamma-enolase; HPRT, hypoxanthine-guanine phosphoribosyltransferase; HSP70, heat-shock-related 70 kDa protein 2; IDHc, cytoplasmic isocitrate dehydrogenase [NADP+]; MAPK1, mitogen-activated protein kinase 1; MEK1, MAP kinase kinase 1; MDHc, cytoplasmic malate dehydrogenase; NFM, neurofilament medium polypeptide; NSF, N-ethylmaleimide-sensitive fusion protein; PHB, prohibitin; PINK1, PTEN-induced putative kinase 1; PPIaseA, peptidyl-prolyl cis-trans isomerase A; PSA2, proteasome subunit alpha type-2; TK, transketolase; VDAC-2, voltage-dependent anion-selective channel protein 2.

    15. Exosome-mediated inflammasome signaling after central nervous system injury

      Juan Pablo de Rivero Vaccari, Frank Brand III, Stephanie Adamczak, Stephanie W. Lee, Jon Perez-Barcena, Michael Y. Wang, M. Ross Bullock, W. Dalton Dietrich and Robert W. Keane

      Article first published online: 1 MAR 2015 | DOI: 10.1111/jnc.13036

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      We propose the following signaling cascade for inflammasome activation in peripheral tissues after CNS injury: CNS trauma induces inflammasome activation in the nervous system and secretion of exosomes containing inflammasome protein cargo into cerebral spinal fluid. The inflammasome containing exosomes then fuse with target cells to activate the innate immune response in peripheral tissues. We suggest that these findings may be used to develop new therapeutics to treat the devastating inflammation and cell destruction evoked by CNS injuries. IL-1β and IL-18 = pro-inflammatory cytokines.

    16. You have full text access to this OnlineOpen article
      Lipid peroxidation is essential for α-synuclein-induced cell death

      Plamena R. Angelova, Mathew H. Horrocks, David Klenerman, Sonia Gandhi, Andrey Y. Abramov and Mikhail S. Shchepinov

      Article first published online: 1 MAR 2015 | DOI: 10.1111/jnc.13024

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      We have found that aggregated α-synuclein-induced production of reactive oxygen species (ROS) that subsequently stimulates lipid peroxidation and cell death in neurons and astrocytes. Specific inhibition of lipid peroxidation by incubation with reinforced polyunsaturated fatty acids (D-PUFAs) completely prevented the effect of α-synuclein on lipid peroxidation and cell death.

    17. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD

      Antonella Tramutola, Judy C. Triplett, Fabio Di Domenico, Dana M. Niedowicz, Michael P. Murphy, Raffaella Coccia, Marzia Perluigi and D. Allan Butterfield

      Article first published online: 26 FEB 2015 | DOI: 10.1111/jnc.13037

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      The figure represents the three different stages of Alzheimer Disease: Preclinical Alzheimer Disease (PCAD), Mild cognitive impairment (MCI) and late stage of Alzheimer Disease. The progression of the disease is associated with a reduction in autophagy (Beclin-1 and LC-3) observed in Inferior parietal lobe of PCAD, MCI, and AD subjects (light red). Related to the autophagy impairment, the graph shows the impairment of PI3K/Akt/mTOR in MCI and AD subjects (dark red).

    18. Molecular determinants of transport stimulation of EAAT2 are located at interface between the trimerization and substrate transport domains

      Ole V. Mortensen, José L. Liberato, Joaquim Coutinho-Netto, Wagner F. dos Santos and Andréia C. K. Fontana

      Article first published online: 26 FEB 2015 | DOI: 10.1111/jnc.13047

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      We identified a domain (purple star) in the glutamate transporter EAAT2 that is important for transport stimulation through a spider venom, and suggest a mechanism for enhanced transporter function through facilitated substrate translocation (arrow). Because the dysfunction of glutamate transporters is implicated in the pathogenesis of neurological disorders, understanding the mechanisms of enhanced transport could have therapeutic implications.

    19. You have full text access to this OnlineOpen article
      A dual role for AMP-activated protein kinase (AMPK) during neonatal hypoxic–ischaemic brain injury in mice

      Catherine I. Rousset, Fiona C. Leiper, Anton Kichev, Pierre Gressens, David Carling, Henrik Hagberg and Claire Thornton

      Article first published online: 24 FEB 2015 | DOI: 10.1111/jnc.13034

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      We show that in an in vivo model of neonatal hypoxia–ischaemic and in oxygen/glucose deprivation in neurons, there is a pathological activation of the CaMKKβ-AMPKα1 signalling pathway. Inhibiting AMPK during OGD promotes neuronal survival; conversely, inhibiting AMPK prior to OGD exacerbates cell death. Our data have clinical relevance as prior sensitization (e.g. exposure to bacterial infection reducing AMPK activity) increases injury. AMPK, AMP-activated protein kinase; HI, hypoxia–ischaemia; OGD, oxygen–glucose deprivation.

    20. Identification of new Presenilin-1 phosphosites: implication for γ-secretase activity and Aβ production

      Alexandre Matz, Blanka Halamoda-Kenzaoui, Romain Hamelin, Sebastien Mosser, Jean-René Alattia, Mitko Dimitrov, Marc Moniatte and Patrick C. Fraering

      Article first published online: 24 FEB 2015 | DOI: 10.1111/jnc.12996

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      In this study, we identified 11 new phosphosites in Presenilin-1 (PS1), the catalytic subunit of the Alzheimer's γ-secretase complex. By combining a mutagenesis approach with cell-based and cell-free γ-secretase assays, we demonstrate that the new phosphosites do not modulate the maturation and activity of γ-secretase. Individual PS1 phosphosites shall thus not be considered therapeutic targets for reducing cerebral Aβ plaque formation in Alzheimer's Disease. Aβ, amyloid beta.

    21. Degradation of gamma secretase activating protein by the ubiquitin–proteasome pathway

      Jin Chu, Jian-Guo Li, Nicholas E. Hoffman, Muniswamy Madesh and Domenico Praticò

      Article first published online: 13 FEB 2015 | DOI: 10.1111/jnc.13011

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      The GSAP derives from a precursor via a caspase 3-mediated cleavage, is up-regulated in Alzheimer's disease brains and facilitates Aβ production by interacting directly with the γ-secretase complex. Here, we demonstrate that GSAP is ubiquitinated and then selectively degraded via the proteasome system but not the calpains or lysosome pathways. These findings provide further evidence for the involvement of the proteasome system in the regulation of amyloid beta (Aβ) precursor protein metabolism and Aβ formation. AICD, APP intracellular domain; APP, amyloid precursor protein; ATP, adenosine triphosphate; CTF-α, alpha-C-terminal fragment; CTF-β, beta-C-terminal fragment; GSAP, γ-secretase activating protein; Ub, ubiquitin.

    22. Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development

      Kristine E. Brown, Gustavo Chagoya, Shawn G. Kwatra, Timothy Yen, Stephen T. Keir, Mary Cooter, Katherine A. Hoadley, Ahmed Rasheed, Eric S. Lipp, Roger Mclendon, Francis Ali-Osman, Darell D. Bigner, John H. Sampson and Madan M. Kwatra

      Article first published online: 12 FEB 2015 | DOI: 10.1111/jnc.13032

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      The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. We validated proteomic profiles using patient-derived glioblastoma xenografts (PDGX), characterizing 20 PDGX models according to subtype classification based on The Cancer Genome Atlas (TCGA) criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. Proteins found to be associated with high EGFR activity represent potential biomarkers for GBM monitoring.

    23. Valproic acid induces neuronal cell death through a novel calpain-dependent necroptosis pathway

      Dominique Bollino, Irina Balan and Laure Aurelian

      Article first published online: 8 FEB 2015 | DOI: 10.1111/jnc.13029

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      A growing body of evidence indicates that valproic acid (VPA) has neurotoxic activity, the mechanism of which is still poorly understood. We report, for the first time, that VPA activates a previously unrecognized calpain-dependent necroptosis cascade that initiates with JNK1 activation and involves AIF cleavage/nuclear translocation and H2AX phosphorylation as well as an altered Smac/DIABLO to XIAP balance.

    24. A novel role for central ACBP/DBI as a regulator of long-chain fatty acid metabolism in astrocytes

      Khalil Bouyakdan, Bouchra Taïb, Lionel Budry, Shangang Zhao, Demetra Rodaros, Ditte Neess, Susanne Mandrup, Nils. J. Faergeman and Thierry Alquier

      Article first published online: 6 FEB 2015 | DOI: 10.1111/jnc.13035

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      Acyl-CoA-binding protein (ACBP) or diazepam-binding inhibitor is a secreted peptide acting centrally as a GABAA allosteric modulator. Using brain slices, cortical, and hypothalamic astrocyte cultures from ACBP KO mice, we demonstrate that ACBP mainly localizes in astrocytes and regulates unsaturated but not saturated long-chain fatty acids (LCFA) metabolism. In addition, ACBP deficiency alters FA metabolism-related genes and results in intracellular FA accumulation while affecting their release. Our results support a novel role for ACBP in brain lipid metabolism. FA, fatty acids; KO, knockout; PL, phospholipids; TAG, triacylglycerol.

    25. Membrane protein oxidation determines neuronal degeneration

      Parvana Hajieva, Nadhim Bayatti, Matthias Granold, Christian Behl and Bernd Moosmann

      Article first published online: 4 FEB 2015 | DOI: 10.1111/jnc.12987

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      Membrane proteins have rarely been investigated as potential victims of oxidative stress in the context of neurodegeneration. This study provides evidence that excessive one-electron oxidation of membrane proteins from within the lipid bilayer, depicted in the graphic, is a functionally decisive step toward neuronal cell death in response to different toxins.

    26. Quantitative positron emission tomography of mGluR5 in rat brain with [18F]PSS232 at minimal invasiveness and reduced model complexity

      Adrienne Müller Herde, Claudia Keller, Selena Milicevic Sephton, Linjing Mu, Roger Schibli, Simon M. Ametamey and Stefanie D. Krämer

      Article first published online: 28 JAN 2015 | DOI: 10.1111/jnc.13001

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      Methods were evaluated to quantify mGluR5 in rat brain by PET with [18F]PSS232. We present a minimally invasive protocol for input function recording. A two-tissue compartment model correcting for radiometabolites at reduced complexity is compared with the standard model. Finally, we demonstrate and explain why for [18F]PSS232 the area-under-the-curve ratio is a valid alternative to the Logan reference tissue analysis.

    27. Exposure to serotonin adversely affects oligodendrocyte development and myelination in vitro

      Lir-Wan Fan, Abhay Bhatt, Lu-Tai Tien, Baoying Zheng, Kimberly L. Simpson, Rick C. S. Lin, Zhengwei Cai, Praveen Kumar and Yi Pang

      Article first published online: 28 JAN 2015 | DOI: 10.1111/jnc.12988

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      The current in vitro study demonstrated that exposure to high level of serotonin (5-HT) led to aberrant oligodendrocyte (OL) development, cell injury, and myelination deficit. We propose that elevated extracellular serotonin levels in the fetal brain, such as upon the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy, may adversely affect OL development and/or myelination, thus contributing to altered neural connectivity seen in Autism Spectrum Disorders. OPC = oligodendrocyte progenitor cell.

    28. Glycine bidirectionally regulates ischemic tolerance via different mechanisms including NR2A-dependent CREB phosphorylation

      Zheng Chen, Bin Hu, Fuzhou Wang, Linlin Du, Baosheng Huang, Lixin Li, Jia Qi and Xiang Wang

      Article first published online: 28 JAN 2015 | DOI: 10.1111/jnc.12994

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      A model of glycine induced dose-dependent bidirectional regulations in ischemic tolerance. (a) Under low dose of Gly pre-treatment, glycine induces NMDAR potentiation and CREB-dependent neuroprotection through the NMDAR co-agonist binding site. (b) Under high dose of Gly pre-treatment, the excessive glycine in synaptic cleft can activate neighboring extrasynaptic sites and combine to the GlyRs. Then, the deteriorative effects would be triggered after NMDAR endocytosis and synaptic depression. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CREB, cAMP response element-binding protein; Gly, glycine; GlyR, glycine receptor; GlyT1, gycine transportor 1; NMDAR, N-methyl-d-aspartate receptor.

    29. 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.

  8. 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.

  9. 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. 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.

    3. 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.

    4. 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.

    5. 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.

    6. 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.

    7. 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.

    8. 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.

    9. 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.

    10. 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.

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