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  • 1
    Online Resource
    Online Resource
    Apoptosis Signal-Regulating Kinase 1 in Amyloid β Peptide-Induced Cerebral Endothelial Cell Apoptosis
    Society for Neuroscience ; 2007
    In:  The Journal of Neuroscience Vol. 27, No. 21 ( 2007-05-23), p. 5719-5729
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 27, No. 21 ( 2007-05-23), p. 5719-5729
    Abstract: A pathological hallmark of Alzheimer's disease is accumulation of amyloid-β peptide (Aβ) in senile plaques. Aβ has also been implicated in vascular degeneration in cerebral amyloid angiopathy because of its cytotoxic effects on non-neuronal cells, including cerebral endothelial cells (CECs). We explore the role of apoptosis signal-regulating kinase 1 (ASK1) in Aβ-induced death in primary cultures of murine CECs. Aβ induced ASK1 dephosphorylation, which could be prevented by selective inhibition of protein phosphatase 2A (PP2A) but not PP2B. ASK1 dephosphorylation resulted in its dissociation from 14-3-3. ASK1, released from 14-3-3 inhibition, activated p38 mitogen-activated protein kinase (p38MAPK), leading to p53 phosphorylation. p53, a proapoptotic transcription factor, in turn transactivated the expression of Bax, a proapoptotic protein. Transfection with various dominant-negative mutants (DNs), including ASK1 DN and p38MAPK DN, suppressed Aβ-induced p38MAPK activation, p53 phosphorylation, and Bax upregulation and partially prevented CEC death. Bax knockdown using a bax small interfering RNA strategy also reduced Bax expression and subsequent CEC death. These results suggest that Aβ activates the ASK1–p38MAPK–p53–Bax cascade to cause CEC death in a PP2A-dependent manner.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1874-06.2007
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2007
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  • 2
    Online Resource
    Online Resource
    Matrix Metalloproteinases Expressed by Astrocytes Mediate Extracellular Amyloid-β Peptide Catabolism
    Society for Neuroscience ; 2006
    In:  The Journal of Neuroscience Vol. 26, No. 43 ( 2006-10-25), p. 10939-10948
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 26, No. 43 ( 2006-10-25), p. 10939-10948
    Abstract: It has been postulated that the development of amyloid plaques in Alzheimer's disease (AD) may result from an imbalance between the generation and clearance of the amyloid-β peptide (Aβ). Although familial AD appears to be caused by Aβ overproduction, sporadic AD (the most prevalent form) may result from impairment in clearance. Recent evidence suggests that several proteases may contribute to the degradation of Aβ. Furthermore, astrocytes have recently been implicated as a potential cellular mediator of Aβ degradation. In this study, we examined the possibility that matrix metalloproteinases (MMPs), proteases known to be expressed and secreted by astrocytes, could play a role in extracellular Aβ degradation. We found that astrocytes surrounding amyloid plaques showed enhanced expression of MMP-2 and MMP-9 in aged amyloid precursor protein (APP)/presenilin 1 mice. Moreover, astrocyte-conditioned medium (ACM) degraded Aβ, lowering levels and producing several fragments after incubation with synthetic human Aβ 1–40 and Aβ 1–42 . This activity was attenuated with specific inhibitors of MMP-2 and -9, as well as in ACM derived from mmp-2 or -9 knock-out (KO) mice. In vivo , significant increases in the steady-state levels of Aβ were found in the brains of mmp-2 and -9 KO mice compared with wild-type controls. Furthermore, pharmacological inhibition of the MMPs with N -[(2 R )-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]- l -tryptophan methylamide (GM 6001) increased brain interstitial fluid Aβ levels and elimination of half-life in APPsw mice. These results suggest that MMP-2 and -9 may contribute to extracellular brain Aβ clearance by promoting Aβ catabolism.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2085-06.2006
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2006
    detail.hit.zdb_id: 1475274-8
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  • 3
    Online Resource
    Online Resource
    The Role of Zinc in Selective Neuronal Death After Transient Global Cerebral Ischemia
    American Association for the Advancement of Science (AAAS) ; 1996
    In:  Science Vol. 272, No. 5264 ( 1996-05-17), p. 1013-1016
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 272, No. 5264 ( 1996-05-17), p. 1013-1016
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.272.5264.1013
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 1996
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
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  • 4
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    Online Resource
    Upregulation of Pleiotrophin Gene Expression in Developing Microvasculature, Macrophages, and Astrocytes after Acute Ischemic Brain Injury
    Society for Neuroscience ; 1998
    In:  The Journal of Neuroscience Vol. 18, No. 10 ( 1998-05-15), p. 3699-3707
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 18, No. 10 ( 1998-05-15), p. 3699-3707
    Abstract: Pleiotrophin (PTN) is a heparin-binding, 18 kDa secretory protein that functions to induce mitogenesis, angiogenesis, differentiation, and transformation in vitro . PTN gene ( Ptn ) expression is highly regulated during development and is highest at sites in which mitogenesis, angiogenesis, and differentiation are active. In striking contrast, with the exception of the neuron, the Ptn gene is only minimally expressed in adults. We now demonstrate that Ptn gene expression is strikingly upregulated within 3 d in OX 42 -positive macrophages, astrocytes, and endothelial cells in areas of developing neovasculature after focal cerebral ischemia in adult rat. Ptn gene expression remains upregulated in these same cells and sites 7 and 14 d after ischemic injury. However, expression of the Ptn gene is significantly decreased in cortical neurons 6 and 24 hr after injury and is undetectable in degenerating neurons at day 3. Neurons in contralateral cortex continue to express Ptn in levels equal to control, uninjured brain. It is suggested that PTN may have a vital role in neovascular formation in postischemic brain and that postischemic brain is an important model in which to analyze sequential gene expression in developing neovasculature. In contrast, Ptn gene expression in injured neurons destined not to recover is strikingly reduced, and potentially its absence may contribute to the failure of the neuron to survive.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.18-10-03699.1998
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 1998
    detail.hit.zdb_id: 1475274-8
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  • 5
    Online Resource
    Online Resource
    Suppression of Postischemic Hippocampal Nerve Growth Factor Expression by a c- fos Antisense Oligodeoxynucleotide
    Society for Neuroscience ; 1999
    In:  The Journal of Neuroscience Vol. 19, No. 4 ( 1999-02-15), p. 1335-1344
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 19, No. 4 ( 1999-02-15), p. 1335-1344
    Abstract: We examined the uptake and distribution of an antisense phosphorothioated oligodeoxynucleotide (s-ODN) to c- fos , rncfosr 115 , infused into the left cerebral ventricle of male Long–Evans rats and the effect of this s-ODN on subsequent Fos, NGF, neurotrophin-3 (NT-3), and actin expression. To establish the uptake and turnover of s-ODN in the brain, we studied the copurification of the immunoreactivity of biotin with biotinylated s-ODN that was recovered from different regions of the brain. A time-dependent diffusion and the localization of s-ODN were further demonstrated by labeling the 3′-OH terminus of s-ODN in situ with digoxigenin-dUTP using terminal transferase and detection using anti-digoxigenin IgG–FITC. Cellular uptake of the s-ODN was evident in both the hippocampal and cortical regions, consistent with a gradient originating at the ventricular surface. Degradation of the s-ODN was observed beginning 48 hr after delivery. The effectiveness of c- fos antisense s-ODN was demonstrated by its suppression of postischemic Fos expression, which was accompanied by an inhibition of ischemia-induced NGF mRNA expression in the dentate gyrus. Infusion of saline, the sense s-ODN, or a mismatch antisense s-ODN did not suppress Fos expression. That this effect of c- fos antisense s-ODN was specific to NGF was demonstrated by its lack of effect on the postischemic expression of the NT-3 and β-actin genes. Our results demonstrate that c- fos antisense s-ODN blocks selected downstream events and support the contention that postischemic Fos regulates the subsequent expression of the NGF gene and that Fos expression may have a functional component in neuroregeneration after focal cerebral ischemia-reperfusion.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.19-04-01335.1999
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 1999
    detail.hit.zdb_id: 1475274-8
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  • 6
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    Tumor Necrosis Factor Receptor Deletion Reduces Nuclear Factor-κB Activation, Cellular Inhibitor of Apoptosis Protein 2 Expression, and Functional Recovery after Traumatic Spinal Cord Injury
    Society for Neuroscience ; 2001
    In:  The Journal of Neuroscience Vol. 21, No. 17 ( 2001-09-01), p. 6617-6625
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 21, No. 17 ( 2001-09-01), p. 6617-6625
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.21-17-06617.2001
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2001
    detail.hit.zdb_id: 1475274-8
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  • 7
    Online Resource
    Online Resource
    STAT5 Mediates Antiapoptotic Effects of Methylprednisolone on Oligodendrocytes
    Society for Neuroscience ; 2009
    In:  The Journal of Neuroscience Vol. 29, No. 7 ( 2009-02-18), p. 2022-2026
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 29, No. 7 ( 2009-02-18), p. 2022-2026
    Abstract: Methylprednisolone (MP), a synthetic glucocorticoid agonist, is widely used for the clinical therapy of white matter diseases in the nervous system, such as spinal cord injury and multiple sclerosis. In addition to its potent anti-inflammatory and antioxidant properties, we recently discovered a selective antiapoptotic effect of MP on oligodendrocytes via the activation of the glucocorticoid receptor (GR) and the upregulation of bcl-X L , a splicing isoform of the bcl-x gene. Based on published findings of the functional interactions between GR and STAT5, a transcription factor from the family of signal transducers and activators of transcription (STAT), we examined whether the glucocorticoid signaling pathway interacts with STAT5 to upregulate bcl-X L and protect oligodendrocytes. We show herein that (1) the GR and STAT5 complex is present on the STAT5-binding site of the bcl-x promoter region in oligodendrocytes; (2) the overexpression of an activated form of STAT5 prevents α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced oligodendrocyte cell death; and (3) this prevention is lost when the STAT5 gene is knocked down. Thus, our results provide one molecular mechanism underlying the postinjury protective effects of oligodendrocytes by stress hormones.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2621-08.2009
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2009
    detail.hit.zdb_id: 1475274-8
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  • 8
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    Online Resource
    Protein Phosphatase 2A Regulates bim Expression via the Akt/FKHRL1 Signaling Pathway in Amyloid-β Peptide-Induced Cerebrovascular Endothelial Cell Death
    Society for Neuroscience ; 2006
    In:  The Journal of Neuroscience Vol. 26, No. 8 ( 2006-02-22), p. 2290-2299
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 26, No. 8 ( 2006-02-22), p. 2290-2299
    Abstract: Amyloid-β peptide (Aβ)-induced death in cerebral endothelial cells (CECs) is preceded by mitochondrial dysfunction and signaling events characteristic of apoptosis. Mitochondria-dependent apoptosis engages Bcl-2 family proteins, especially the BH3-only homologues, which play a key role in initiating the apoptotic cascade. Here, we report that the expression of bim , but not other BH3-only members, was selectively increased in cerebral microvessels isolated from 18-month-old APPsw (Tg2576) mice, a model of cerebral amyloid angiopathy (CAA), suggesting a pivotal role for Bim in Aβ-induced cerebrovascular degeneration in vivo . A similar expression profile was observed in Aβ-treated CECs. Furthermore, Aβ induction of bim expression involved a pro-apoptotic transcription factor, FKHRL1. FKHRL1 bound to a consensus sequence in the bim promoter region and was activated by Aβ before bim expression. FKHRL1 activity was negatively regulated by phosphorylation catalyzed by Akt, an anti-apoptotic kinase. Akt upregulation by adenoviral gene transfer inhibited Aβ-induced FKHRL1 activation and bim induction. In addition, Aβ increased the activity of protein phosphatase 2A (PP2A), a ceramide-activated protein phosphatase. Suppression of PP2A activity by RNA interference or a specific inhibitor, okadaic acid, effectively suppressed Aβ-induced Akt inactivation and FKHRL1 activation, leading to an attenuation of bim expression and cell death in CECs. Coimmunoprecipitation experiments revealed that Aβ enhanced the binding of the PP2A regulatory subunit PP2ACαβ to Akt. These results implicate PP2A as an early regulator of Aβ-induced bim expression and CEC apoptosis via the Akt/FKHRL1 signaling pathway. We raise the possibility that this pathway may play a role in cerebrovascular degeneration in CAA.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5103-05.2006
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2006
    detail.hit.zdb_id: 1475274-8
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  • 9
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    Methylprednisolone Protects Oligodendrocytes But Not Neurons after Spinal Cord Injury
    Society for Neuroscience ; 2008
    In:  The Journal of Neuroscience Vol. 28, No. 12 ( 2008-03-19), p. 3141-3149
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 28, No. 12 ( 2008-03-19), p. 3141-3149
    Abstract: Methylprednisolone (MP) is used to treat a variety of neurological disorders involving white matter injury, including multiple sclerosis, acute disseminated encephalomyelitis, and spinal cord injury (SCI). Although its mechanism of action has been attributed to anti-inflammatory or antioxidant properties, we examined the possibility that MP may have direct neuroprotective activities. Neurons and oligodendrocytes treated with AMPA or staurosporine died within 24 h after treatment. MP attenuated oligodendrocyte death in a dose-dependent manner; however, neurons were not rescued by the same doses of MP. This protective effect was reversed by the glucocorticoid receptor (GR) antagonist (11, 17)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one (RU486) and small interfering RNA directed against GR, suggesting a receptor-dependent mechanism. MP reversed AMPA-induced decreases in the expression of anti-apoptotic Bcl-x L , caspase-3 activation, and DNA laddering, suggesting anti-apoptotic activity in oligodendrocytes. To examine whether MP demonstrated this selective protection in vivo , neuronal and oligodendrocyte survival was assessed in rats subjected to spinal cord injury (SCI); groups of rats were treated with or without MP in the presence or absence of RU486. Eight days after SCI, MP significantly increased oligodendrocytes (CC-1-immunoreactive cells) after SCI, but neuronal (neuronal-specific nuclear protein-immunoreactive cells) number remained unchanged; RU486 reversed this protective effect. MP also inhibited SCI-induced decreases in Bcl-x L and caspase-3 activation. Consistent with these findings, the volume of demyelination, assessed by Luxol fast blue staining, was attenuated by MP and reversed by RU486. These results suggest that MP selectively inhibits oligodendrocyte but not neuronal cell death via a receptor-mediated action and may be a mechanism for its limited protective effect after SCI.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5547-07.2008
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2008
    detail.hit.zdb_id: 1475274-8
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  • 10
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    Glucocorticoid Receptor-Mediated Suppression of Activator Protein-1 Activation and Matrix Metalloproteinase Expression after Spinal Cord Injury
    Society for Neuroscience ; 2001
    In:  The Journal of Neuroscience Vol. 21, No. 1 ( 2001-01-01), p. 92-97
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 21, No. 1 ( 2001-01-01), p. 92-97
    Abstract: Post-traumatic inflammatory reaction may contribute to progressive tissue damage after spinal cord injury (SCI). Two key transcription factors, nuclear factor κB (NF-κB) and activator protein-1 (AP-1), are activated in inflammation. An increase in NF-κB binding activity has been shown in the injured spinal cord. We report activation of AP-1 after SCI. Electrophoretic mobility shift assay showed that AP-1 binding activity increased after SCI, starting at 1 hr, peaking at 8 hr, and declining to basal levels by 7 d. Methylprednisolone (MP) is the only therapeutic agent approved by the Food and Drug Administration for treating patients with acute traumatic SCI. MP reduced post-traumatic AP-1 activation. RU486, a glucocorticoid receptor (GR) antagonist, reversed MP inhibition of AP-1 activation. Immunostaining showed an increase in the expression of the Fos-B and c-Jun components of AP-1 in the injured cord. A c-fos antisense oligodeoxynucleotide (ODN) inhibited AP-1, but not NF-κB, activation after SCI. AP-1 and NF-κB can transactivate genes encoding matrix metalloproteinase-1 (MMP-1) and MMP-9. Western blotting and immunostaining show increased expression of MMP-1 and MMP-9 in the injured cord. MP inhibited MMP-1 and MMP-9 expression after SCI. RU486 reversed this MP effect. The c-fos antisense ODN, however, failed to suppress MMP-1 or MMP-9 expression. These findings demonstrate that MP may suppress post-traumatic inflammatory reaction by inhibiting both the AP-1 and NF-κB transcription cascades via a GR mechanism. Expression of inflammatory genes such as MMP-1 and MMP-9 that are transactivated jointly by AP-1 and NF-κB may not be suppressed by inhibiting only AP-1 activity.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.21-01-00092.2001
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2001
    detail.hit.zdb_id: 1475274-8
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