bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long‐lasting acetylcholinesterase splice variations in anticholinesterase‐treated Alzheimer's disease patients
Authors: Darreh‐Shori T. , Hellström‐Lindahl E. , Flores‐Flores C. , Guan Z. Z. , Soreq H. , Nordberg A. 
Published: February 2004

AbstractProtein levels of different acetylcholinesterase (AChE) splice variants were explored by a combination of immunoblot techniques, using two different antibodies, directed against the C‐terminus of the AChE‐R splice variant or the core domain common to all variants. Both AChE‐R and AChE‐S splice variants as well as several heavier AChE complexes were detected in brain homogenates from the parietal cortex of patients with or without Alzheimer's disease (AD) as well as the cerebrospinal fluid (CSF) of AD patients, compatible with the assumption that CSF AChEs might originate from CNS neurons. Long‐term changes in the composition of CSF AChE variants were further pursued in AD patients treated with rivastigmine (n = 11) or tacrine (n = 17) in comparison to untreated AD patients (n = 5). In untreated patients, AChE‐R was markedly reduced as compared with the baseline level (37%), whereas the medium size AChE‐S complex was increased by 32%. Intriguingly, tacrine produced a general and profound up‐regulation of all detected AChE variants (up to 117%), whereas rivastigmine treatment caused a mild and selective up‐regulation of AChE‐R (∼10%, p < 0.05). Moreover, the change in the ratio of AChE‐R to AChE‐S (R/S‐ratio) strongly and positively correlated with sustained cognition at 12 months (p < 0.0001). Thus, evaluation of changes in the composition of CSF AChE variants may yield important information referring to the therapeutic efficacy and/or development of drug tolerance in AD patients treated with anti‐cholinesterases.
A restrictive element 1 (RE‐1) in the VIP gene modulates transcription in neuronal and non‐neuronal cells in collaboration with an upstream tissue specifier element
Authors: Hamelink Carol , Hahm Sung Ho , Huang Heather , Eiden Lee E. 
Published: February 2004

AbstractThe vasoactive intestinal peptide (VIP) gene has been studied extensively as a prototype neuronal gene containing multiple cis‐active elements that confer responsiveness to cell lineage, neurotrophic, and activity‐dependent intrinsic and extrinsic cues. However, reporter genes containing the presumptive complete regulatory region 5′ to the start of transcription do not confer tissue‐specific gene expression in vivo. We therefore sought cis‐regulatory elements downstream of the transcriptional start that might confer additional tissue‐specific and tissue‐restrictive properties to the VIP transcriptional unit. We report here a repressor element, similar to the canonical restrictive element‐1 (RE‐1), located within the first non‐coding exon of the human VIP gene. The ability of this element to regulate VIP reporter gene expression in neuroblastoma and fibroblastic cells was examined. Endogenous VIP expression is high in SH‐EP neuroblastoma cells, low but inducible in SH‐SY5Y cells, and absent in HeLa cells. Endogenous RE‐1 silencer factor (REST) expression was highest in SH‐EP and HeLa cells, and significantly lower in SH‐SY5Y cells. Transient transfection of a VIP reporter gene containing a mutated RE‐1 sequence revealed an RE‐1‐dependent regulation of VIP gene expression in all three cell types, with regulation greatest in cells (SH‐EP, HeLa) with highest levels of REST expression. Serial truncation of the VIP reporter gene further revealed a specific interaction between the RE‐1 and a tissue‐specifier element located 5 kb upstream in the VIP gene. Thus, REST can regulate VIP gene expression in both neuroblastic and non‐neuronal cells, but requires coupling to the upstream tissue specifier element.
Region‐specific generation of functional neurons from naive embryonic stem cells in adult brain
Authors: Harkany Tibor , Andäng Michael , Kingma Hylke Jan , Görcs Tamás J. , Holmgren Carl D. , Zilberter Yuri , Ernfors Patrik 
Published: February 2004

AbstractEmbryonic stem (ES) cells are multipotent progenitors with unlimited developmental potential, and in vitro differentiated ES cell‐derived neuronal progenitors can develop into functional neurons when transplanted in the central nervous system. As the capacity of naive primary ES cells to integrate in the adult brain and the role of host neural tissue therein are yet largely unknown, we grafted low densities of undifferentiated mouse ES (mES) cells in adult mouse brain regions associated with neurodegenerative disorders; and we demonstrate that ES cell‐derived neurons undergo gradual integration in recipient tissue and acquire morphological and electrophysiological properties indistinguishable from those of host neurons. Only some brain areas permitted survival of mES‐derived neural progenitors and formed instructive environments for neuronal differentiation and functional integration of naive mES cells. Hence, region‐specific presence of microenvironmental cues and their pivotal involvement in controlling ES cell integration in adult brain stress the importance of recipient tissue characteristics in formulating cell replacement strategies for neurodegenerative disorders.
Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin
Authors: Albertson Dawn N. , Pruetz Barb , Schmidt Carl J. , Kuhn Donald M. , Kapatos Gregory , Bannon Michael J. 
Published: February 2004

AbstractChronic cocaine abuse induces long‐term neural adaptations as a consequence of alterations in gene expression. This study was undertaken to identify those transcripts differentially regulated in the nucleus accumbens of human cocaine abusers. Affymetrix microarrays were used to measure transcript abundance in 10 cocaine abusers and 10 control subjects matched for age, race, sex, and brain pH. As expected, gene expression of cocaine‐ and amphetamine‐regulated transcript (CART) was increased in the nucleus accumbens of cocaine abusers. The most robust and consistent finding, however, was a decrease in the expression of a number of myelin‐related genes, including myelin basic protein (MBP), proteolipid protein (PLP), and myelin‐associated oligodendrocyte basic protein (MOBP). The differential expression seen by microarray for CART as well as MBP, MOBP, and PLP was verified by RT–PCR. In addition, immunohistochemical experiments revealed a decrease in the number of MBP‐immunoreactive oligodendrocytes present in the nucleus accumbens and surrounding white matter of cocaine abusers. These findings suggest a dysregulation of myelin in human cocaine abusers.
D1 dopamine receptor stimulation increases the rate of AMPA receptor insertion onto the surface of cultured nucleus accumbens neurons through a pathway dependent on protein kinase A
Authors: Mangiavacchi Simona , Wolf Marina E. 
Published: February 2004

AbstractTrafficking of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate (AMPA) receptors is an important determinant of synaptic strength. Our prior work suggests that D1 dopamine (DA) receptors regulate AMPA receptor trafficking. This is a possible mechanism by which amphetamine and cocaine, which indirectly stimulate D1 receptors, may alter synaptic strength in addiction‐related neuronal circuits. Post‐natal rat nucleus accumbens (NAc) cultures were used to study the role of protein kinase A (PKA) in D1 receptor regulation of the surface expression of the AMPA receptor subunit GluR1. Using an immunocytochemical assay that selectively detects newly externalized GluR1, we found that the rate of GluR1 externalization is enhanced by the D1 agonist SKF 81297 (100 nm‐1 µm). This was blocked by a D1 receptor antagonist (SCH 23390; 10 µm) and by two different cell‐permeable PKA inhibitors, KT5720 (2 and 10 µm) and RpcAMPS (10 µm). Conversely, the PKA activator SpcAMPS increased the rate of GluR1 externalization in a concentration‐dependent manner. A maximally effective concentration of SpcAMPS (10 µm) occluded the effect of SKF 81297 (1 µm) on GluR1 externalization. Using similar cultures, we showed previously that D1 receptor stimulation increases GluR1 phosphorylation at the PKA site. Together, our findings suggest that PKA phosphorylation of GluR1 is required for GluR1 externalization in response to D1 receptor stimulation.
Effect of tissue transglutaminase on the solubility of proteins containing expanded polyglutamine repeats
Authors: Lai T.‐S. , Tucker T. , Burke J. R. , Strittmatter W. J. , Greenberg C. S. 
Published: February 2004

SummaryThe expansion of a polyglutamine (polyQ) domain in neuronal proteins is the molecular genetic cause of at least eight neurodegenerative diseases. Proteins with a polyQ domain that is greater than 40 Q (Q40) residues form insoluble intranuclear and cytoplasmic inclusions. Expanded polyQ proteins self‐associate by non‐covalent interactions and become insoluble. They can also be covalently cross‐linked by tissue transglutaminase (TTG), a calcium‐dependent enzyme present in cells throughout the nervous system. However, it remains unclear whether TTG cross‐linking directly contributes to the insolubility of the expanded polyQ proteins. Using an in vitro solubility assay, we found TTG cross‐linked Q62 monomers into high molecular weight soluble complexes in a calcium‐dependent reaction. Inhibition of TTG cross‐linking by primary amine substrates including putrescine and biotinylated pentylamine antagonized TTG's ability to form soluble complexes. In contrast, primary amines (histamine and lysine) that were less effective inhibitors of TTG cross‐linking did not inhibit Q62 from becoming insoluble. In summary, TTG can increase the solubility of expanded polyQ proteins by catalyzing intermolecular cross‐links. This demonstrates directly that TTG will reduce the ability of expanded polyQ proteins from becoming insoluble. Furthermore, the effectiveness of a primary amine substrate at inhibiting formation of insoluble inclusions may be related to their ability to inhibit intermolecular cross‐linking by TTG.
Mitochondrial calcium, oxidative stress and apoptosis in a neurodegenerative disease model induced by 3‐nitropropionic acid
Authors: Rosenstock T. R. , Carvalho A. C. P. , Jurkiewicz A. , Frussa‐Filho R. , Smaili S. S. 
Published: February 2004

AbstractIntracellular calcium homeostasis is important for cell survival. However, increase in mitochondrial calcium (Ca2+m) induces opening of permeability transition pore (PTP), mitochondrial dysfunction and apoptosis. Since alterations of intracellular Ca2+ and reactive oxygen species (ROS) generation are involved in cell death, they might be involved in neurodegenerative processes such as Huntington's disease (HD). HD is characterized by the inhibition of complex II of respiratory chain and increase in ROS production. In this report, we studied the correlation between the inhibitor of the complex II, 3‐nitropropionic acid (3NP), Ca2+ metabolism, apoptosis and behavioural alterations. We showed that 3NP (1 mm) is able to release Ca2+m, as neither Thapsigargin (TAP, 2 µm) nor free‐calcium medium affected its effect. PTP inhibitors and antioxidants inhibited this process, suggesting an increase in ROS generation and PTP opening. In addition, 3NP (0.1 mm) also induces apoptotic cell death. Behavioural changes in animals treated with 3NP (20 mg/kg/day for 4 days) were also attenuated by pre‐ and co‐treatment with vitamin E (VE, 20 mg/kg/day). Taken together, our results show that complex II inhibition could involve Ca2+m release, oxidative stress and cell death that may precede motor alterations in neurodegenerative processes such as HD.
In vivo modulation of extracellular hippocampal glutamate and GABA levels and limbic seizures by group I and II metabotropic glutamate receptor ligands
Authors: Smolders Ilse , Lindekens Hilde , Clinckers Ralph , Meurs Alfred , O'Neill Michael J. , Lodge David , Ebinger Guy , Michotte Yvette 
Published: February 2004

AbstractThe effects of several metabotropic receptor (mGluR) ligands on baseline hippocampal glutamate and GABA overflow in conscious rats and the modulation of limbic seizure activity by these ligands were investigated. Intrahippocampal mGluR group I agonist perfusion via a microdialysis probe [1 mm (R,S)‐3,5‐dihydroxyphenylglycine] induced seizures and concomitant augmentations in amino acid dialysate levels. The mGlu1a receptor antagonist LY367385 (1 mm) decreased baseline glutamate but not GABA concentrations, suggesting that mGlu1a receptors, which regulate hippocampal glutamate levels, are tonically activated by endogenous glutamate. This decrease in glutamate may contribute to the reported LY367385‐mediated anticonvulsant effect. The mGlu5 receptor antagonist 2‐methyl‐6‐(phenylethynyl)‐pyridine (50 mg/kg) also clearly abolished pilocarpine‐induced seizures. Agonist‐mediated actions at mGlu2/3 receptors by LY379268 (100 µm, 10 mg/kg intraperitoneally) decreased basal hippocampal GABA but not glutamate levels. This may partly explain the increased excitation following systemic LY379268 administration and the lack of complete anticonvulsant protection within our epilepsy model with the mGlu2/3 receptor agonist. Group II selective mGluR receptor blockade with LY341495 (1–10 µm) did not alter the rats' behaviour or hippocampal amino acid levels. These data provide a neurochemical basis for the full anticonvulsant effects of mGlu1a and mGlu5 antagonists and the partial effects observed with mGlu2/3 agonists in vivo.
AICA riboside both activates AMP‐activated protein kinase and competes with adenosine for the nucleoside transporter in the CA1 region of the rat hippocampus
Authors: Gadalla Anne E. , Pearson Tim , Currie Ailsa J. , Dale Nicholas , Hawley Simon A. , Sheehan Mike , Hirst Warren , Michel Anton D. , Randall Andrew , Hardie D. Grahame , Frenguelli Bruno G. 
Published: February 2004

Abstract5‐Aminoimidazole‐4‐carboxamide riboside (AICA riboside; Acadesine) activates AMP‐activated protein kinase (AMPK) in intact cells, and is reported to exert protective effects in the mammalian CNS. In rat cerebrocortical brain slices, AMPK was activated by metabolic stress (ischaemia > hypoxia > aglycaemia) and AICA riboside (0.1–10 mm). Activation of AMPK by AICA riboside was greatly attenuated by inhibitors of equilibrative nucleoside transport. AICA riboside also depressed excitatory synaptic transmission in area CA1 of the rat hippocampus, which was prevented by an adenosine A1 receptor antagonist and reversed by application of adenosine deaminase. However, AICA riboside was neither a substrate for adenosine deaminase nor an agonist at adenosine receptors. We conclude that metabolic stress and AICA riboside both stimulate AMPK activity in mammalian brain, but that AICA riboside has an additional effect, i.e. competition with adenosine for uptake by the nucleoside transporter. This results in an increase in extracellular adenosine and subsequent activation of adenosine receptors. Neuroprotection by AICA riboside could be mediated by this mechanism as well as, or instead of, by AMPK activation. Caution should therefore be exercised in ascribing an effect of AICA riboside to AMPK activation, especially in systems where inhibition of adenosine re‐uptake has physiological consequences.
Modulation ofnurr1gene expression in mesencephalic dopaminergic neurones
Authors: Volpicelli Floriana , Perrone‐Capano Carla , Da Pozzo Paola , Colucci‐D'Amato Luca , Di Porzio Umberto 
Published: February 2004

AbstractThe transcription factor/nuclear receptor Nurr1 is essential for the differentiation of midbrain dopaminergic neurones. Here we demonstrate that, during the ontogeny of rat ventral mesencephalon,nurr1gene expression is developmentally regulated and its levels show a sharp peak between embryonic day E13 and E15, when most dopaminergic neurones differentiate. In addition, in primary cultures from embryonic rat mesencephalon,nurr1gene follows a temporal pattern of expression comparable to that observedin vivo. We also report that exposure of embryonic mesencephalic cultures to depolarizing stimuli leads to a robust increase innurr1mRNA and protein. The depolarizing effect is also detected in mesencephalic cultures enriched in dopaminergic neurones by using a combination of bFGF and Sonic hedgehog. The latter further increases the number of dopaminergic neurones in these ‘expanded’ cultures, an effect abolished in the presence of anti‐Sonic hedgehog antibodies. Our data show thatnurr1gene is highly expressed in midbrain dopaminergic neurones in a sharp temporal window and that its expression is plastic, bothin vivoandin vitro. In addition we show that Sonic hedgehog can direct dopaminergic differentiation in proliferating dopaminergic neuroblastsin vitro.
Mutant superoxide dismutase 1 causes motor neuron degeneration independent of cyclin‐dependent kinase 5 activation by p35 or p25
Authors: Takahashi Satoru , Kulkarni Ashok B. 
Published: February 2004

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective loss of motor neurons in the brain and spinal cord. Neurotoxicity mediated by glutamate is thought to play a role in the neuronal death through intracellular calcium‐dependent signaling cascades. Cyclin‐dependent kinase 5 (Cdk5) has been proposed as one of the calcium‐dependent mediators that may cause neuronal death observed in this disease. Cdk5 is activated in neurons by the association with its activators, p35 or p39. The calcium‐activated protease calpain cleaves p35 to its truncated product, p25, which eventually causes the cellular mislocalization and prolonged activation of Cdk5. This deregulated Cdk5 induces cytoskeletal disruption and apoptosis. To examine whether inhibition of the calpain‐mediated conversion of p35 to p25 can delay the disease progression of ALS, we generated double transgenic mice in which ALS‐linked mutant copper/zinc superoxide dismutase 1 (SOD1G93A) was expressed in a p35‐null background. The absence of p35 neither affected the onset and progression of motor neuron disease in the mutant SOD1 mice nor ameliorated the pathological lesions in these mice. Our results provide direct evidence that the pathogenesis of motor neuron disease in the mutant SOD1 mice is independent of the Cdk5 activation by p35 or p25.
The neurotrophic effect of oleic acid includes dendritic differentiation and the expression of the neuronal basic helix‐loop‐helix transcription factor NeuroD2
Authors: Rodríguez‐Rodríguez Rosa A. , Tabernero Arantxa , Velasco Ana , Lavado Eva M. , Medina José M. 
Published: February 2004

AbstractWe have shown recently that the presence of albumin in astrocytes triggers the synthesis and release of oleic acid, which behaves as a neurotrophic factor for neurons. Thus, oleic acid promotes axonal growth together with the expression of the axonal growth‐associated protein, GAP‐43. Here we attempted to elucidate whether the neurotrophic effect of oleic acid includes dendritic differentiation. Our results indicate that oleic acid induces the expression of microtubule associated protein‐2 (MAP‐2), a marker of dendritic differentiation. In addition, the presence of oleic acid promotes the translocation of MAP‐2 from the soma to the dendrites. The time course of MAP‐2 expression during brain development coincides with that of stearoyl‐CoA desaturase, the limiting enzyme of oleic acid synthesis, indicating that both phenomena coincide during development. The effect of oleic acid on MAP‐2 expression is most probably independent of autocrine factors synthesized by neurons because this effect was also observed at low cellular densities. As oleic acid is an activator of protein kinase C, the possible participation of this transduction pathway was studied. Our results indicate that added oleic acid or oleic acid endogenously synthesized by astrocytes exerts its neurotrophic effect through a protein kinase C‐dependent mechanism as the effect was inhibited by sphingosine or two myristoylated peptide inhibitors of protein kinase C. The transduction pathway by which oleic acid induces the expression of genes responsible for neuronal differentiation appears to be mediated by the transcription factor NeuroD2, a regulator of terminal neuronal differentiation.
Stimulus‐ and cell‐type‐specific release of purines in cultured rat forebrain astrocytes and neurons
Authors: Parkinson Fiona E. , Xiong Wei 
Published: February 2004

AbstractAdenosine is formed during conditions that deplete ATP, such as ischemia. Adenosine deaminase converts adenosine into inosine, and both adenosine and inosine can be beneficial for postischemic recovery. This study investigated adenosine and inosine release from astrocytes and neurons during chemical hypoxia or oxygen–glucose deprivation. In both cell types, 2‐deoxyglucose was the most effective stimulus for depleting cellular ATP and for evoking inosine release; in contrast, oxygen–glucose deprivation evoked the greatest adenosine release. α,β‐Methylene ADP, an inhibitor of ecto‐5′nucleotidase, significantly reduced adenosine release from astrocytes but not neurons. Dipyridamole, an inhibitor of equilibrative nucleoside transporters, inhibited both adenosine and inosine release from neurons. Erythro‐9‐(2‐hydroxy‐3‐nonyl)adenine, an inhibitor of adenosine deaminase, reduced neuronal inosine release evoked by oxygen–glucose deprivation but not by 2‐deoxyglucose treatment. These data indicate that (1) astrocytes release adenine nucleotides that are hydrolyzed extracellularly to adenosine, whereas neurons release adenosine per se, (2) inosine is formed intracellularly and released via nucleoside transporters, and (3) inosine is formed by an adenosine deaminase‐dependent pathway during oxygen–glucose deprivation but not during 2‐deoxyglucose treatment. In summary, the metabolic pathways for adenosine formation and release were cell‐type dependent whereas the pathways for inosine formation were stimulus dependent.
Expression of glucose transporter isoform GLUT‐2 and glucokinase genes in human brain
Authors: Roncero Isabel , Alvarez Elvira , Chowen Julie A. , Sanz Carmen , Rábano Alberto , Vázquez Patricia , Blázquez Enrique 
Published: February 2004

AbstractThe glucose transporter isoform‐2 (GLUT‐2) and glucokinase are considered to be components of a glucose sensor system controlling several key processes, and hence may modulate feeding behaviour. We have found GLUT‐2 and glucokinase mRNAs in several brain regions, including the ventromedial and arcuate nuclei of the hypothalamus. GLUT‐2, glucokinase and glucokinase regulatory protein mRNAs and proteins were present in these areas as determined by biochemical approaches. In addition, glucose‐phosphorylating activity with a high apparent Km for glucose that displayed no product inhibition by glucose‐6‐phosphate was observed. Increased glycaemia after meals may be recognized by specific hypothalamic neurones due to the high Km of GLUT‐2 and glucokinase. This enzyme is considered to be the true glucose sensor because it catalyses the rate‐limiting step of glucose catabolism its activity being regulated by interaction with glucokinase regulatory protein, that functions as a metabolic sensor.