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  • 1
    Keywords: CELLS ; CELL ; POPULATION ; GENE ; PROTEIN ; transcription ; TRANSCRIPTION FACTOR ; REDUCTION ; animals ; cell cycle ; CELL-CYCLE ; CYCLE ; MOUSE ; MUTANT ; NERVOUS-SYSTEM ; etiology ; REGION ; REGIONS ; EMBRYO ; PHENOTYPE ; PROGENITOR CELLS ; REGULATOR ; LAYER ; EMBRYOS ; DENTATE GYRUS ; ADULT ; CORTEX ; NEURONS ; FOREBRAIN DEVELOPMENT ; BETA-TUBULIN ISOTYPE ; BrdU ; DEVELOPING MOUSE NEOCORTEX ; lamination ; limbic system ; MURINE CEREBRAL WALL ; NEURAL STEM-CELLS ; neurogenesis ; PROLIFERATIVE EPITHELIUM ; tailless ; VENTRICULAR ZONE
    Abstract: The tailless (tlx) gene is a forebrain-restricted transcription factor. Tlx mutant animals exhibit a reduction in the size of the cerebral hemispheres and associated structures ( Monaghan et al., 1997). Superficial cortical layers are specifically reduced, whereas deep layers are relatively unaltered ( Land and Monaghan, 2003). To determine whether the adult laminar phenotype has a developmental etiology and whether it is associated with a change in proliferation/differentiation decisions, we examined the cell cycle and neurogenesis in the embryonic cortex. We found that there is a temporal and regional requirement for the Tlx protein in progenitor cells (PCs). Neurons prematurely differentiate at all rostrocaudal levels up to mid-neurogenesis in mutant animals. Heterozygote animals have an intermediate phenotype indicating there is a threshold requirement for Tlx in early cortical neurogenesis. Our studies indicate that PCs in the ventricular zone are sensitive to loss of Tlx in caudal regions only; however, PCs in the subventricular zone are altered at all rostrocaudal levels in tlx-deficient animals. Furthermore, we found that the cell cycle is shorter from embryonic day 9.5 in tlx(-/-) embryos. At mid-neurogenesis, the PC population becomes depleted, and late PCs have a longer cell cycle in tlx-deficient animals. Consequently, later generated structures, such as upper cortical layers, the dentate gyrus, and the olfactory bulbs, are severely reduced. These studies indicate that tlx is an essential intrinsic regulator in the decision to proliferate or differentiate in the developing forebrain
    Type of Publication: Journal article published
    PubMed ID: 15385616
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  • 2
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; PATHWAY ; VITRO ; DEATH ; GENE ; PROTEIN ; RNA ; LINES ; gene transfer ; GENE-TRANSFER ; MECHANISM ; RAT ; CONTRAST ; mechanisms ; CELL-LINES ; PROTEIN-KINASE ; CLEAVAGE ; resistance ; CD95 ligand ; CELL-DEATH ; INDUCED APOPTOSIS ; MEMBRANE ; LINE ; KAPPA-B ; sensitivity ; OVEREXPRESSION ; cell lines ; CASPASE-8 CLEAVAGE ; SIGNALING COMPLEX ; CASPASE ; INHIBITORS ; RE ; GLIOMA ; CASPASE-8 ; OLIGONUCLEOTIDE ; NEURONS ; C-FLIP ; cell death ; ANTISENSE OLIGONUCLEOTIDE ; AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME ; CEREBELLAR GRANULE NEURONS ; Fas/CD95 ; IMMUNE PRIVILEGE ; lifeguard ; PHOSPHATIDYLINOSITOL 3-KINASE ; PI3-kinase/ Akt
    Abstract: The contribution of Fas (CD95/APO-1) to cell death mechanisms of differentiated neurons is controversially discussed. Rat cerebellar granule neurons (CGNs) express high levels of Fas in vitro but are resistant to FasL (CD95L/APO-1L/CD178)-induced apoptosis. We here show that this resistance was mediated by a phosphatidylinositol 3-kinase (PI3-kinase)-Akt/protein kinase B (PKB)-dependent expression of lifeguard (LFG)/neuronal membrane protein 35. Reduction of endogenous LFG expression by antisense oligonucleotides or small interfering RNA lead to increased sensitivity of CGNs to FasL-induced cell death and caspase-8 cleavage. The inhibition of PI3-kinase activity sensitized CGNs to FasL-induced caspase-8 and caspase-3 processing and caspase-dependent fodrin cleavage. Pharmacological inhibition of PI3-kinase, overexpression of the inhibitory protein I kappa B, or cotransfection of an LFG reporter plasmid with dominant-negative Akt/PKB inhibited LFG reporter activity, whereas overexpression of constitutively active Akt/PKB increased LFG reporter activity. Overexpression of LFG in CGNs interfered with the sensitization to FasL by PI3-kinase inhibitors. In contrast to CGNs, 12 glioma cell lines, which are sensitive to FasL, did not express LFG. Gene transfer of LFG into these FasL-susceptible glioma cells protected against FasL-induced apoptosis. These results demonstrate that LFG mediated the FasL resistance of CGNs and that, under certain circumstances, e. g., inhibition of the PI3-kinase-Akt/PKB pathway, CGNs were sensitized to FasL
    Type of Publication: Journal article published
    PubMed ID: 16033886
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  • 3
    Keywords: IN-VITRO ; SURVIVAL ; human ; INHIBITION ; VITRO ; SYSTEM ; PROTEIN ; transcription ; DIFFERENTIATION ; MICE ; TRANSCRIPTION FACTOR ; PHOSPHORYLATION ; ELEMENT-BINDING PROTEIN ; NERVOUS-SYSTEM ; TRANSCRIPTION FACTORS ; TRANSGENIC MICE ; immunohistochemistry ; MIGRATION ; PROGENITOR CELLS ; TRACER ; ADULT ; MICE LACKING ; NEURONS ; cell survival ; SPINE ; development ; PHASE ; ADULT MAMMALIAN BRAIN ; adult neurogenesis ; cell differentiation ; CREB PHOSPHORYLATION ; downregulation ; GENERATED NEURONS ; NEURONAL DIFFERENTIATION ; olfactory deafferentation ; PHENOTYPIC DIFFERENTIATION ; radial migration ; SUBEPENDYMAL ZONE ; SUBVENTRICULAR ZONE
    Abstract: The transcription factor cAMP response element-binding protein ( CREB) is involved in multiple aspects of neuronal development and plasticity. Here, we demonstrate that CREB regulates specific phases of adult neurogenesis in the subventricular zone/olfactory bulb (SVZ/OB) system. Combining immunohistochemistry with bromodeoxyuridine treatments, cell tracer injections, cell transplants, and quantitative analyses, we show that although CREB is expressed by the SVZ neuroblasts throughout the neurogenic process, its phosphorylation is transient and parallels neuronal differentiation, increasing during the late phase of tangential migration and decreasing after dendrite elongation and spine formation. In vitro, inhibition of CREB function impairs morphological differentiation of SVZ-derived neuroblasts. Transgenic mice lacking CREB, in a null CREM genetic background, show reduced survival of newborn neurons in the OB. This finding is further supported by peripheral afferent denervation experiments resulting in downregulation of CREB phosphorylation in neuroblasts, the survival of which appears heavily impaired. Together, these findings provide evidence that CREB regulates differentiation and survival of newborn neurons in the OB
    Type of Publication: Journal article published
    PubMed ID: 16267218
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  • 4
    Keywords: brain ; EXPRESSION ; Germany ; DEATH ; PROTEIN ; METABOLISM ; MICE ; DNA ; MECHANISM ; animals ; mechanisms ; fibroblasts ; DISORDER ; ALZHEIMERS-DISEASE ; GLUTATHIONE ; PLASMA ; MUTATION ; REPAIR ; RATES ; PATHOGENESIS ; DIET ; DEMENTIA ; BEHAVIOR ; ANTIOXIDANT ; MEMORY IMPAIRMENT ; DENTATE GYRUS ; STROKE ; DEFICIENCY ; DISORDERS ; ADULT ; review ; fibroblast ; MICE LACKING ; NEURONS ; neurogenesis ; LEVEL ; NUCLEAR ; INDUCE ; GENOTYPE ; PSYCHIATRIC-DISORDERS ; USA ; HOMOCYSTEINE ; depression ; neurodegeneration ; animal ; DEGENERATION ; base excision repair ; DYSFUNCTION ; ADULT HIPPOCAMPAL NEUROGENESIS ; despair ; folate deficiency ; FOLIC-ACID DEFICIENCY ; MAJOR DEPRESSIVE DISORDER ; MILD CEREBRAL-ISCHEMIA ; MITOCHONDRIAL-DNA ; NEURAL-TUBE DEFECTS ; NEURONAL CELL-DEATH ; OXYGEN SPECIES PRODUCTION ; PLASMA HOMOCYSTEINE LEVELS
    Abstract: Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegenerative conditions like stroke and dementia. Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression. We hypothesized that the pathogenic mechanisms include uracil misincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (Ung(-/-)) versus wild-type controls. Folate depletion increased nuclear mutation rates in Ung(-/-) embryonic fibroblasts, and conferred death of cultured Ung(-/-) hippocampal neurons. Feeding animals a folate-deficient diet (FD) for 3 months induced degeneration of CA3 pyramidal neurons in Ung(-/-) but not Ung(-/-) mice along with decreased hippocampal expression of brain-derived neurotrophic factor protein and decreased brain levels of antioxidant glutathione. Furthermore, FD induced cognitive deficits and mood alterations such as anxious and despair-like behaviors that were aggravated in Ung(-/-) mice. Independent of Ung genotype, FD increased plasma homocysteine levels, altered brain monoamine metabolism, and inhibited adult hippocampal neurogenesis. These results indicate that impaired uracil repair is involved in neurodegeneration and neuropsychiatric dysfunction induced by experimental folate deficiency
    Type of Publication: Journal article published
    PubMed ID: 18614692
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  • 5
    Keywords: APOPTOSIS ; CELLS ; GROWTH ; proliferation ; SURVIVAL ; CELL ; Germany ; INHIBITION ; SYSTEM ; DEATH ; GENE ; GENES ; RNA ; transcription ; MICE ; ACTIVATION ; TRANSCRIPTION FACTOR ; INDUCTION ; hippocampus ; NERVOUS-SYSTEM ; TRANSCRIPTIONAL ACTIVITY ; DISRUPTION ; CELL-DEATH ; STRESS ; inactivation ; p53 ; STRATEGIES ; INTERACTS ; HEALTHY ; molecular ; ADULT ; RE ; FACTOR TIF-IA ; NEURONS ; ABLATION ; LEVEL ; cell death ; nucleolus ; RNA polymerase I ; progenitor ; INDUCE ; USA ; LOSSES ; neurodegeneration ; PROGENITORS ; DEGENERATION ; NOV ; response ; synthesis ; POLYMERASE ; STATE ; RNA-POLYMERASE ; neural progenitors ; rRNA transcription ; TRANSCRIPTION ACTIVITY
    Abstract: Transcription of rRNA genes is essential for maintaining nucleolar integrity, a hallmark for the healthy state and proliferation rate of a cell. Inhibition of rRNA synthesis leads to disintegration of the nucleolus, elevated levels of p53, and induction of cell suicide, identifying the nucleolus as a critical stress sensor. Whether deregulation of rRNA synthesis is causally involved in neurodegeneration by promoting cell death and/or by inhibiting cellular growth has however not been addressed. The transcription factor TIF-IA plays a central role in mammalian rRNA synthesis, regulating the transcriptional activity of RNA polymerase I. To investigate the consequences of nucleolar perturbation in the nervous system, we have chosen to specifically ablate the gene encoding the transcription factor TIF-IA in two different contexts: neural progenitors and hippocampal neurons. Here, we show that ablation of TIF-IA leads to impaired nucleolar activity and results in increased levels of the proapoptotic transcription factor p53 in both neural progenitors and hippocampal neurons but induces rapid apoptosis only in neural progenitors. Nondividing cells of the adult hippocampus are more refractory to loss of rRNA transcription and face a protracted degeneration. Our study provides an unexploited strategy to initiate neurodegeneration based on perturbation of nucleolar function and underscores a novel perspective to study the cellular and molecular changes involved in the neurodegenerative processes
    Type of Publication: Journal article published
    PubMed ID: 19036968
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  • 6
    Keywords: IN-VIVO ; THERAPY ; LONG-TERM POTENTIATION ; synaptic plasticity ; METABOTROPIC GLUTAMATE RECEPTORS ; CUE-INDUCED REINSTATEMENT ; CULTURED STRIATAL NEURONS ; DIFFERENTIAL INVOLVEMENT ; KNOCK-OUT MICE ; NUCLEUS-ACCUMBENS CORE ; PAVLOVIAN APPROACH BEHAVIOR
    Abstract: Understanding the psychobiological basis of relapse remains a challenge in developing therapies for drug addiction. Relapse in cocaine addiction often occurs following exposure to environmental stimuli previously associated with drug taking. The metabotropic glutamate receptor, mGluR5, is potentially important in this respect; it plays a central role in several forms of striatal synaptic plasticity proposed to underpin associative learning and memory processes that enable drug-paired stimuli to acquire incentive motivational properties and trigger relapse. Using cell type-specific RNA interference, we have generated a novel mouse line with a selective knock-down of mGluR5 in dopamine D1 receptor-expressing neurons. Although mutant mice self-administer cocaine, we show that reinstatement of cocaine-seeking induced by a cocaine-paired stimulus is impaired. By examining different aspects of associative learning in the mutant mice, we identify deficits in specific incentive learning processes that enable a reward-paired stimulus to directly reinforce behavior and to become attractive, thus eliciting approach toward it. Our findings show that glutamate signaling through mGluR5 located on dopamine D1 receptor-expressing neurons is necessary for incentive learning processes that contribute to cue-induced reinstatement of cocaine-seeking and which may underpin relapse in drug addiction
    Type of Publication: Journal article published
    PubMed ID: 20826661
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  • 7
    Abstract: Gamma frequency oscillations in cortical regions can be recorded during cognitive processes, including attention or memory tasks. These oscillations are generated locally as a result of reciprocal interactions between excitatory pyramidal cells and perisomatic inhibitory interneurons. Here, we examined the contribution of the three perisomatic interneuron types-the parvalbumin-containing fast-spiking basket cells (FSBCs) and axo-axonic cells (AACs), as well as the cholecystokinin-containing regular-spiking basket cells (RSBCs) to cholinergically induced oscillations in hippocampal slices, a rhythmic activity that captures several features of the gamma oscillations recorded in vivo. By analyzing the spiking activities of single neurons recorded in parallel with local field potentials, we found that all three cell types fired phase locked to the carbachol-induced oscillations, although with different frequencies and precision. During these oscillations, FSBCs fired the most with the highest accuracy compared with the discharge of AACs and RSBCs. In further experiments, we showed that activation of my-opioid receptors by DAMGO ([D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin acetate), which significantly reduced the inhibitory, but not excitatory, transmission, suppressed or even blocked network oscillations both in vitro and in vivo, leading to the desynchronization of pyramidal cell firing. Using paired recordings, we demonstrated that carbachol application blocked GABA release from RSBCs and reduced it from FSBCs and AACs, whereas DAMGO further suppressed the GABA release only from FSBCs, but not from AACs. These results collectively suggest that the rhythmic perisomatic inhibition, generating oscillatory fluctuation in local field potentials after carbachol treatment of hippocampal slices, is the result of periodic GABA release from FSBCs.
    Type of Publication: Journal article published
    PubMed ID: 21068319
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  • 8
    Keywords: CAENORHABDITIS-ELEGANS ; APOLIPOPROTEIN-E ; NEURITE OUTGROWTH ; OXIDATIVE STRESS ; HYDROGEN-PEROXIDE ; PICHIA-PASTORIS ; BETA-PROTEIN ; A-BETA ; CEREBROSPINAL-FLUID LIPOPROTEINS ; PRIMARY NEURONAL CULTURES
    Abstract: The amyloid precursor protein (APP) of Alzheimer's disease (AD) has a copper binding domain (CuBD) located in the N-terminal cysteine-rich region that can strongly bind copper(II) and reduce it to Cu(I) in vitro. The CuBD sequence is similar among the APP family paralogs [amyloid precursor-like proteins (APLP1 and APLP2)] and its orthologs (including Drosophila melanogaster, Xenopus laevis, and Caenorhabditis elegans), suggesting an overall conservation in its function or activity. The APP CuBD is involved in modulating Cu homeostasis and amyloid beta peptide production. In this paper, we demonstrate for the first time that Cu-metallated full-length APP ectodomain induces neuronal cell death in vitro. APP Cu neurotoxicity can be induced directly or potentiated through Cu(I)-mediated oxidation of low-density lipoprotein, a finding that may have important implications for the role of lipoproteins and membrane cholesterol composition in AD. Cu toxicity induced by human APP, Xenopus APP, and APLP2 CuBDs is dependent on conservation of histidine residues at positions corresponding to 147 and 151 of human APP. Intriguingly, APP orthologs with different amino acid residues at these positions had dramatically altered Cu phenotypes. The corresponding C. elegans APL-1 CuBD, which has tyrosine and lysine residues at positions 147 and 151, respectively, strongly protected against Cu-mediated lipid peroxidation and neurotoxicity in vitro. Replacement of histidines 147 and 151 with tyrosine and lysine residues conferred this neuroprotective Cu phenotype to human APP, APLP2, and Xenopus APP CuBD peptides. Moreover, we show that the toxic and protective CuBD phenotypes are associated with differences in Cu binding and reduction. These studies identify a significant evolutionary change in the function of the CuBD in modulating Cu metabolism. Our findings also suggest that targeting of inhibitors to histidine residues at positions 147 and 151 of APP could significantly alter the oxidative potential of APP.
    Type of Publication: Journal article published
    PubMed ID: 11784781
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  • 9
    Keywords: EXPRESSION ; ALZHEIMERS-DISEASE ; LONG-TERM POTENTIATION ; CELL-ADHESION MOLECULE ; polysialic acid ; CONDITIONED FEAR ; ADULT DENTATE GYRUS ; AGONIST D-CYCLOSERINE ; AUDITORY-EVOKED POTENTIALS ; COUPLED GLYCINE RECEPTOR ; D-ASPARTATE RECEPTORS
    Abstract: Neural cell adhesion molecule (NCAM) is the predominant carrier of the unusual glycan polysialic acid (PSA). Deficits in PSA and/or NCAM expression cause impairments in hippocampal long-term potentiation and depression (LTP and LTD) and are associated with schizophrenia and aging. In this study, we show that impaired LTP in adult NCAM-deficient (NCAM(-/-)) mice is restored by increasing the activity of the NMDA subtype of glutamate receptor (GluN) through either reducing the extracellular Mg(2+) concentration or applying d-cycloserine (DCS), a partial agonist of the GluN glycine binding site. Pharmacological inhibition of the GluN2A subtype reduced LTP to the same level in NCAM(-/-) and wild-type (NCAM(+/+)) littermate mice and abolished the rescue by DCS in NCAM(-/-) mice, suggesting that the effects of DCS are mainly mediated by GluN2A. The insufficient contribution of GluN to LTD in NCAM(-/-) mice was also compensated for by DCS. Furthermore, impaired contextual and cued fear conditioning levels were restored in NCAM(-/-) mice by administration of DCS before conditioning. In 12-month-old NCAM(-/-), but not NCAM(+/+) mice, there was a decline in LTP compared with 3-month-old mice that could be rescued by DCS. In 24-month-old mice of both genotypes, there was a reduction in LTP that could be fully restored by DCS in NCAM(+/+) mice but only partially restored in NCAM(-/-) mice. Thus, several deficiencies of NCAM(-/-) mice can be ameliorated by enhancing GluN2A-mediated neurotransmission with DCS.
    Type of Publication: Journal article published
    PubMed ID: 22396402
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  • 10
    Keywords: COMPLEX ; TRAFFICKING ; RNA INTERFERENCE ; APP ; ACTIVATING-FACTOR-ACETYLHYDROLASE ; GAMMA-SECRETASE ACTIVITY ; ALPHA-SECRETASE ; ONSET ALZHEIMERS-DISEASE ; TRANSGENIC DROSOPHILA ; PEPTIDE GENERATION
    Abstract: Amyloid-beta peptide (A beta) is believed to play a central role in the pathogenesis of Alzheimer's disease. In view of the side effects associated with inhibiting the secretases that produce A beta, new molecular targets are required to provide alternative therapeutic options. We used RNA interference (RNAi) to systematically screen the Drosophila genome to identify genes that modulate A beta production upon knockdown. RNAi of 41 genes in Drosophila cells significantly lowered A beta without affecting general secretion or viability. After the gamma-secretase complex components, the most potent effect was observed for platelet activating factor acetylhydrolase alpha (Paf-AH alpha), and, in mammalian cells, the effect was replicated for its ortholog PAFAH1B2. Knockdown of PAFAH1B2 strongly reduced A beta secretion from human cells, and this effect was confirmed in primary cells derived from PAFAH1B2 knock-out mice. Reduced A beta production was not attributable to altered beta-amyloid precursor protein (APP) ectodomain shedding but was a result of an enhanced degradation of APP C-terminal fragments (CTFs) in the absence of PAFAH1B2 but not its close homolog PAFAH1B3. Enhanced degradation of APP CTFs was selective because no such effects were obtained for Notch or E-/N-cadherin. Thus, we have identified an important protein that can selectively modify A beta generation via a novel mechanism, namely enhanced degradation of its immediate precursor. In view of the absence of a neurological phenotype in PAFAH1B2 knock-out mice, targeted downregulation of PAFAH1B2 may be a promising new strategy for lowering A beta.
    Type of Publication: Journal article published
    PubMed ID: 23238734
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