14 results on '"Gliosis genetics"'
Search Results
2. Heterozygous knockout of cytosolic phospholipase A 2α attenuates Alzheimer's disease pathology in APP/PS1 transgenic mice.
- Author
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Qu B, Gong Y, Gill JM, Kenney K, and Diaz-Arrastia R
- Subjects
- Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Peptides genetics, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor biosynthesis, Amyloid beta-Protein Precursor genetics, Animals, Brain metabolism, Cell Membrane physiology, Cytosol enzymology, Cytosol metabolism, Disease Models, Animal, Glial Fibrillary Acidic Protein biosynthesis, Glial Fibrillary Acidic Protein genetics, Gliosis genetics, Gliosis metabolism, Group IV Phospholipases A2 metabolism, Heterozygote, Humans, Mice, Mice, Knockout, Mice, Transgenic, Microglia enzymology, Microglia metabolism, Microglia pathology, Plaque, Amyloid genetics, Plaque, Amyloid metabolism, Plaque, Amyloid pathology, Presenilin-1 biosynthesis, Presenilin-1 genetics, Alzheimer Disease enzymology, Alzheimer Disease genetics, Group IV Phospholipases A2 deficiency, Group IV Phospholipases A2 genetics
- Abstract
Cytosolic phospholipase A2α (cPLA2α) is a key enzyme in regulation of inflammation process and neuromembrane homeostasis, both of which are critical in pathogenesis of Alzheimer's diseases. By hybride APP/PS1 Tg-AD mice with cPLA2α knockout mice, three lines of APP/PS1 Tg-AD mice were produced with genotypes of cPLA2α
+/+ , cPLA2α+/- and cPLA2α-/- . Compared to cPLA2α+/+ Tg-AD mice, the amyloid plaque formation was significantly downregulated in the brain of cPLA2α+/- Tg-AD mice, but not in cPLA2α-/- Tg-AD mice. The reactive gliosis were also significantly downregulated in both cPLA2α+/- and cPLA2α-/- Tg-AD mouse lines. The paradoxical effects of cPLA2α on the amyloid plaques reveal a complex role of cPLA2α in pathogenesis of AD and could be a potential target for prevention and treatment of AD., (Published by Elsevier B.V.)- Published
- 2017
- Full Text
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3. Contribution of Rag1 to spatial memory ability in rats.
- Author
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Fang M, Yin Y, Chen H, Hu Z, Davies H, and Ling S
- Subjects
- Animals, Animals, Genetically Modified, Blotting, Western, Cells, Cultured, Electrophysiological Phenomena, Female, Fluorescent Antibody Technique, Genetic Vectors, Gliosis genetics, Gliosis pathology, Hippocampus metabolism, Hippocampus physiology, Homeodomain Proteins genetics, Immunohistochemistry, Lentivirus genetics, Maze Learning physiology, Pregnancy, RNA, Messenger biosynthesis, RNA, Messenger genetics, RNA, Small Interfering genetics, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Stereotaxic Techniques, Transduction, Genetic, Homeodomain Proteins physiology, Memory physiology, Space Perception physiology
- Abstract
Rag1 plays a critical role in the development and maturation of lymphocytes, and is related to immune memory functions. Deletion of Rag1 results in a lack of mature functional B and T lymphocytes. Rag1 transcription is most apparent in regions of the postnatal brain with high neuronal cell density--the cerebellum and the hippocampal formation, both of which are relevant to learning and memory function. In this research, three pairs of shRNA targeting Rag1 and a pair of scrambled sequences were constructed, packaged within a lentiviral vector system, and transferred into the cultured rat hippocampal neuron cells in vitro. Meanwhile, the lentivirus was injected stereotaxically into CA3 of the rat hippocampus, where the positive immunofluorescence for GFP expression was located. Rag1 mRNA expression was detected by RT-PCR 7, 14 and 28 days after stereotaxic injection. Assessment in the Morris water maze test 28 days post stereotaxic injection showed a loss of spatial learning and memory in the experimental rats. In long-term potentiation research, the experimental group did not display remarkable disparity in comparison with the control group. These findings indicate that the knockdown of Rag1 expression in the hippocampus may impair spatial learning and memory ability in rats., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
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4. No association of the C>T polymorphism that is located 1385 upstream from initial code of fibroblast growth factor 1 gene with Alzheimer's disease in Chinese.
- Author
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Bian JT, Zhao HL, Zhang ZX, Bi XH, and Zhang JW
- Subjects
- Adult, Age of Onset, Aged, Aged, 80 and over, Alzheimer Disease ethnology, Alzheimer Disease metabolism, Apolipoprotein E4 genetics, Astrocytes metabolism, Astrocytes pathology, Base Sequence genetics, DNA Mutational Analysis, Female, Gene Frequency genetics, Genetic Predisposition to Disease ethnology, Genetic Testing, Genotype, Gliosis genetics, Gliosis pathology, Gliosis physiopathology, Humans, Male, Middle Aged, Point Mutation genetics, Sex Distribution, Alzheimer Disease genetics, Asian People genetics, Fibroblast Growth Factor 1 genetics, Genetic Predisposition to Disease genetics, Polymorphism, Genetic genetics
- Abstract
Several lines of evidence indicate that fibroblast growth factor 1 (FGF1) confers neuroprotection against excitotocity and contributes to the selective vulnerability of neurons in entorhinal cortex in Alzheimer's disease (AD). Especially, FGF1 is related to Apolipoprotein E (ApoE) expression in reactive astrocytes. Therefore, FGF1 is a promising candidate gene for AD. Two studies reported the association of a polymorphism that is located 1385bp upstream from the initial code of FGF1 gene (FGF1 -1385 C>T) polymorphism with AD. To determine whether this polymorphism could affect AD development, we investigated the association between this polymorphism and AD risk in 372 sporadic AD patients and 349 controls in a Chinese Han population. No significant difference of allele and genotype distributions between the AD cases and the controls was observed in the total samples (for the alleles, chi(2)=0.126; p=0.722; for the genotypes, chi(2)=0.089; p=0.765), neither when the samples were stratified by ApoE epsilon4-carrying status, age/age at onset and gender. Our data suggested no association between the FGF1 -1385 C>T polymorphism and AD risk in Chinese Han population., (Copyright 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
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5. Excitatory amino acid transporter expression by astrocytes is neuroprotective against microglial excitotoxicity.
- Author
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Liang J, Takeuchi H, Doi Y, Kawanokuchi J, Sonobe Y, Jin S, Yawata I, Li H, Yasuoka S, Mizuno T, and Suzumura A
- Subjects
- Amino Acid Transport Systems, Acidic metabolism, Animals, Astrocytes cytology, Astrocytes drug effects, Cell Communication drug effects, Cell Communication genetics, Cells, Cultured, Coculture Techniques, Cytoprotection drug effects, Excitatory Amino Acid Transporter 1 genetics, Excitatory Amino Acid Transporter 1 metabolism, Excitatory Amino Acid Transporter 2 genetics, Excitatory Amino Acid Transporter 2 metabolism, Excitatory Amino Acid Transporter 3 genetics, Excitatory Amino Acid Transporter 3 metabolism, Excitatory Amino Acid Transporter 4 genetics, Excitatory Amino Acid Transporter 4 metabolism, Excitatory Amino Acid Transporter 5 genetics, Excitatory Amino Acid Transporter 5 metabolism, Gliosis genetics, Gliosis metabolism, Gliosis physiopathology, Glutamic Acid metabolism, Glutamic Acid pharmacology, Mice, Mice, Inbred C57BL, Microglia cytology, Microglia drug effects, Nerve Degeneration genetics, Nerve Degeneration physiopathology, RNA, Messenger metabolism, Amino Acid Transport Systems, Acidic genetics, Astrocytes metabolism, Cytoprotection genetics, Microglia metabolism, Nerve Degeneration metabolism, Neurotoxins metabolism
- Abstract
Glutamate-induced excitotoxicity is considered as a major cause of neurodegenerative disease. Excitatory amino acid transporters (EAATs) on glial cells are responsible for the homeostasis of extracellular glutamate in the central nervous system which may contribute to the prevention of excitotoxic neurodegeneration. However, the differential EAAT expression in astrocytes and microglia is not fully understood. In this study, we compared the expression of EAATs in astrocytes and microglia, and we assessed the neuroprotective and neurotoxic function of astrocytes and microglia by a co-culture system. RT-PCR analyses detected that astrocytes expressed each EAAT (EAAT1-5) whereas microglia did not express EAAT4. Western blot analyses demonstrated that astrocytes express a much larger amount of membrane-localized EAATs than microglia. Astrocytes prevented excito-neurotoxicity by the reduction of exogenous glutamate whereas microglia did not. Conversely, activated microglia released an excess of glutamate that induced excitotoxic neuronal death. Astrocytes rescued neurons from microglial glutamate-induced death in a ratio-dependent manner. Inhibition of EAATs abolished glutamate uptake and the neuroprotective effect of astrocytes, but it did not alter any microglial neurotoxic or neuroprotective effects. These results revealed that astrocytic EAATs can counteract microglial glutamate-induced neuronal death whereas microglial EAATs are inconsequential to neurotoxicity and neuroprotection.
- Published
- 2008
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6. ORMOSIL nanoparticles as a non-viral gene delivery vector for modeling polyglutamine induced brain pathology.
- Author
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Klejbor I, Stachowiak EK, Bharali DJ, Roy I, Spodnik I, Morys J, Bergey EJ, Prasad PN, and Stachowiak MK
- Subjects
- Animals, Brain metabolism, Brain pathology, Brain physiopathology, DNA Repeat Expansion genetics, Disease Models, Animal, Ectodysplasins analysis, Ectodysplasins biosynthesis, Female, Gliosis genetics, Gliosis metabolism, Gliosis physiopathology, Huntington Disease genetics, Huntington Disease metabolism, Huntington Disease physiopathology, Injections, Intraventricular, Male, Mice, Mice, Transgenic, Nanoparticles toxicity, Nerve Degeneration genetics, Nerve Degeneration metabolism, Nerve Degeneration physiopathology, Peptides metabolism, Peptides toxicity, Plasmids genetics, Rats, Rats, Wistar, Silicon Dioxide, Gene Transfer Techniques trends, Genetic Vectors genetics, Nanoparticles chemistry, Peptides genetics, Siloxanes pharmacology, Transfection methods
- Abstract
Studies have shown the presence of expanded polyQ containing proteins in brain cells related to Huntington disease (HD) and other poly-glutamine disorders. We report the use of organically modified silica (ORMOSIL) nanoparticles as an efficient non-viral gene carrier in an effort to model brain pathology associated with those disorders induced by expanded polyQ peptides. In experiment 1, plasmids expressing Hemaglutinin-tagged polypeptides with 20 glutamine repeats (Q20) or with extended 127-glutamine repeats (Q127) were complexed with ORMOSIL nanoparticles and injected twice (2 weeks apart) into the lateral ventricle of the mouse brain. Fourteen days post-injection of Q127, immunocytochemistry revealed the presence of the characteristic nuclear and cytoplasmic Q127 aggregates in numerous striatal, septal and neocortical neuronal cells as well as ubiquitin-containing aggregates indicative of the neuronal pathology. The mice receiving Q127 showed a marked increase in the reactive GFAP (+) astrocytes in striatum, septum and brain cortex, further indicating the neurodegenerative changes, accompanied by motor impairments. In experiment 2, plasmids Q20 or Q127 were complexed with ORMOSIL and were injected into the brain lateral ventricle or directly into the striatum of adult rats. In both routes of transfection, Q127 induced the appearance of reactive GFAP (+) astrocytes and activated ED1 antigen expressing microglia. An increase in the size of the lateral ventricle was also observed in rats receiving Q127. In transgenic mouse polyQ models, extensive pathologies occur outside the nervous system and the observed brain pathologies could reflect developmental effects of the toxic polyQ proteins. Our experiments show that the nervous tissue restricted expression of poly Q-extended peptides in adult brain is sufficient to evoke neuropathologies associated with HD and other polyQ disorders. Thus, nanotechnology can be employed to model pathological and behavioral aspects of genetic brain diseases in mice as well as in other species, providing a novel research tool for in vivo testing of single or multi-gene therapies.
- Published
- 2007
- Full Text
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7. Osteopontin expression in substantia nigra in MPTP-treated primates and in Parkinson's disease.
- Author
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Iczkiewicz J, Jackson MJ, Smith LA, Rose S, and Jenner P
- Subjects
- Aged, Aged, 80 and over, Animals, Callithrix, Cell Survival physiology, Disease Models, Animal, Dopamine metabolism, Down-Regulation physiology, Encephalitis genetics, Encephalitis metabolism, Encephalitis physiopathology, Female, Gliosis genetics, Gliosis metabolism, Gliosis physiopathology, Humans, Male, Middle Aged, Nerve Degeneration genetics, Nerve Degeneration metabolism, Nerve Degeneration physiopathology, Neuroglia metabolism, Osteopontin genetics, Oxidative Stress physiology, Parkinson Disease genetics, Parkinson Disease physiopathology, Parkinsonian Disorders genetics, Parkinsonian Disorders physiopathology, RNA, Messenger metabolism, Substantia Nigra physiopathology, Neurons metabolism, Osteopontin metabolism, Parkinson Disease metabolism, Parkinsonian Disorders metabolism, Substantia Nigra metabolism
- Abstract
Parkinson's disease (PD) is characterised by the loss of dopaminergic neurones in the substantia nigra (SN) but the pathogenic mechanism remains unknown. Cell death involves oxidative stress and inflammatory mechanisms, and these may be altered by the actions of the glycosylated phosphoprotein osteopontin (OPN). OPN is present in the rat SN, but its presence in human and non-human primate brain has not been extensively studied. Both OPN mRNA and protein were present in the normal marmoset SN, and OPN protein was localised to nigral neurones although these were not dopaminergic cells and it was not present in glial cells. In contrast, OPN protein was found in dopaminergic neurones in the normal human SN but again not in glial cells with some accumulation in the extracellular matrix. Following MPTP treatment of common marmosets, OPN protein expression was decreased, although its mRNA levels were unchanged and it was not present in either activated microglia or astrocytes. In the SN in PD, OPN protein expression was decreased in the remaining dopaminergic neurones and it was present in activated microglia but not in astrocytes. This was not specific to PD as OPN protein expression was also decreased in the SN in multiple system atrophy and progressive supranuclear palsy with an identical localisation of the protein. The presence of OPN in the normal human and non-human primate SN coupled to its decreased expression following nigral cell degeneration suggests that it may play an important role in dopaminergic neurone survival.
- Published
- 2006
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8. A novel membrane protein, encoded by the gene covering KIAA0233, is transcriptionally induced in senile plaque-associated astrocytes.
- Author
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Satoh K, Hata M, Takahara S, Tsuzaki H, Yokota H, Akatsu H, Yamamoto T, Kosaka K, and Yamada T
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease physiopathology, Animals, Base Sequence, Cell Line, Tumor, Cells, Cultured, Encephalitis genetics, Encephalitis physiopathology, Endoplasmic Reticulum metabolism, Endoplasmic Reticulum ultrastructure, Gene Expression Regulation genetics, Gliosis genetics, Gliosis physiopathology, Golgi Apparatus metabolism, Golgi Apparatus ultrastructure, Humans, Ion Channels, Membrane Proteins genetics, Membrane Proteins isolation & purification, Molecular Sequence Data, Plaque, Amyloid genetics, RNA, Messenger metabolism, Rats, Sequence Homology, Amino Acid, Transcriptional Activation genetics, Up-Regulation genetics, Alzheimer Disease metabolism, Astrocytes metabolism, Encephalitis metabolism, Gliosis metabolism, Membrane Proteins metabolism, Plaque, Amyloid metabolism
- Abstract
Beta-amyloid (Abeta) deposition and senile plaque-associated astrocytes are common neuropathological features of Alzheimer's disease (AD). Although the molecular mechanisms by which Abeta contributes to the progression of neuropathologic changes have not been entirely established, there is little doubt that the association of Abeta with astrocytes, the predominant cell type in brain, significantly influences exacerbation of the disease. In an effort to identify astrocyte-derived molecules that may be intimately associated with progression of AD, we identified a novel Abeta-induced rat gene, designated Mib, whose human counterpart covers KIAA0233. Mib-transfected C6 cells express Mib protein in the endoplasmic reticulum and endplasmic reticulum-Golgi-intermediate compartment. To evaluate roles of Mib in AD, we investigated its expression in the AD brain. In non-AD brains, Mib mRNA has been detected in neurons but not in quiescent astrocytes. On the contrary, in AD brains, Mib mRNA is expressed in activated astrocytes associated with senile plaques, but not expressed in neurons around lesions. From these observations, Mib appears to be a novel Abeta-responsive gene that may play a role in astrocyte inflammatory activation around senile plaques in the AD brain.
- Published
- 2006
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9. The pathophysiology of traumatic brain injury in alpha7 nicotinic cholinergic receptor knockout mice.
- Author
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Kelso ML, Wehner JM, Collins AC, Scheff SW, and Pauly JR
- Subjects
- Acetylcholine metabolism, Adaptation, Physiological genetics, Animals, Binding Sites genetics, Binding, Competitive genetics, Brain Hemorrhage, Traumatic complications, Brain Hemorrhage, Traumatic genetics, Cerebral Cortex pathology, Cognition Disorders drug therapy, Cognition Disorders genetics, Disease Models, Animal, Down-Regulation genetics, Encephalitis genetics, Encephalitis metabolism, Encephalitis physiopathology, Female, Genetic Predisposition to Disease genetics, Genotype, Gliosis genetics, Gliosis metabolism, Gliosis physiopathology, Male, Mice, Mice, Knockout, Microglia cytology, Microglia metabolism, Nerve Degeneration genetics, Nerve Degeneration metabolism, Nerve Degeneration physiopathology, Synaptic Transmission genetics, alpha7 Nicotinic Acetylcholine Receptor, Brain Hemorrhage, Traumatic physiopathology, Cerebral Cortex metabolism, Cerebral Cortex physiopathology, Cognition Disorders physiopathology, Receptors, Nicotinic genetics
- Abstract
The alpha7 nicotinic cholinergic receptor is a ligand-gated ion channel with calcium permeability similar to that of ionotrophic glutamate receptors. Previous studies from our laboratory have implicated changes in expression alpha7 nicotinic cholinergic receptors in the pathophysiology of traumatic brain injury (TBI). In rats, TBI causes a time-dependent and significant decrease in cortical and hippocampal alpha-[(125)I]-bungarotoxin (BTX) binding. We have postulated that deficits in alpha7 expression may contribute to TBI-induced cognitive impairment and that nicotinic receptor agonists can reverse alpha7 binding deficits and result in significant cognitive improvement compared to saline-treated controls. Thus, alpha7 nAChRs could be involved in a form of cholinergically mediated excitotoxicity following brain injury. In the current study, wild-type, heterozygous and null mutant mice were employed to test the hypothesis that genotypic depletion of the alpha7 receptor would render animals less sensitive to tissue loss and brain inflammation following experimental brain injury. Mice were anesthetized and subjected to a 0.5-mm cortical contusion injury of the somatosensory cortex. Brain inflammation, changes in nicotinic receptor expression and cortical tissue sparing were evaluated in wild-type, heterozygous and homozygous mice 1 week following TBI. In wild-type mice, brain injury caused a significant decrease in BTX binding in several hippocampal regions, consistent with what we have measured in rat brain following TBI. However, there were no genotypic differences in cortical tissue sparing or brain inflammation in this experiment. Although the results of this study were largely negative, it is still plausible that changes in the activity/expression of native alpha7 receptors contribute to pathophysiology following TBI. However, when null mutant mice develop in the absence of central alpha7 expression, it is possible that compensatory changes occur that confound the results obtained.
- Published
- 2006
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10. Compromised reactive microgliosis in MPTP-lesioned IL-6 KO mice.
- Author
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Cardenas H and Bolin LM
- Subjects
- Animals, Astrocytes metabolism, Astrocytes pathology, Gliosis genetics, Immunohistochemistry, Interleukin-6 genetics, Male, Mice, Mice, Knockout, Microglia metabolism, Microglia pathology, Models, Animal, Nitric Oxide Synthase biosynthesis, Nitric Oxide Synthase Type II, Parkinsonian Disorders genetics, Substantia Nigra metabolism, Gliosis pathology, Interleukin-6 deficiency, Parkinsonian Disorders pathology, Substantia Nigra pathology
- Abstract
Reactive gliosis, the cellular manifestation of neuroinflammation, is a pathological hallmark of neurodegenerative diseases including Parkinson's disease. The persistent gliosis observed in the Parkinson's disease substantia nigra (SN) and in humans and animals exposed to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) may represent a chronic inflammatory response that contributes to pathology. We have previously shown that in the absence of interleukin-6 (IL-6) dopaminergic neurons are more vulnerable to MPTP. Since IL-6 is both an autocrine and paracrine proliferation factor for CNS glia, we investigated reactive gliosis in MPTP-lesioned IL-6 (-/-) mice. While astrogliosis was similar in injured IL-6 (+/+) and IL-6 (-/-) SN pars compacta (pc), microgliosis was severely compromised in IL-6 (-/-) mice. In the absence of IL-6, an acute reactive microgliosis was transient with a complete absence of reactive microglia at day 7 post-lesion. Extensive reactive microgliosis was observed in the SNpc of MPTP-lesioned IL-6 (+/+) mice. Because glial derived inducible nitric oxide synthase (iNOS) has been implicated in dopaminergic cell death, we examined glial iNOS expression in the IL-6 genotypes to determine if it correlated with the greater vulnerability and reduced microgliosis observed in the MPTP-lesioned IL-6 (-/-) nigrostriatal system. Both reactive microglia and astrocytes expressed iNOS in the lesioned SNpc. In the IL-6 (-/-) mice, microglial iNOS expression diminished as reactive microgliosis declined. The data suggest IL-6 regulation of microglia activation, while iNOS expression appears to be secondary to cell activation.
- Published
- 2003
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11. Inhibition of calpain-mediated apoptosis by E-64 d-reduced immediate early gene (IEG) expression and reactive astrogliosis in the lesion and penumbra following spinal cord injury in rats.
- Author
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Ray SK, Matzelle DD, Wilford GG, Hogan EL, and Banik NL
- Subjects
- Animals, Apoptosis physiology, Astrocytes drug effects, Astrocytes metabolism, Astrocytes pathology, Calpain metabolism, Carrier Proteins drug effects, Carrier Proteins metabolism, Caspase 3, Caspases genetics, Cysteine Proteinase Inhibitors therapeutic use, DNA Fragmentation drug effects, DNA Fragmentation physiology, Female, Genes, Immediate-Early physiology, Glial Fibrillary Acidic Protein genetics, Gliosis drug therapy, Gliosis genetics, Gliosis physiopathology, Leucine therapeutic use, Microfilament Proteins drug effects, Microfilament Proteins metabolism, Proto-Oncogene Proteins c-fos genetics, Proto-Oncogene Proteins c-jun genetics, RNA, Messenger drug effects, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Spinal Cord drug effects, Spinal Cord pathology, Spinal Cord physiopathology, Spinal Cord Injuries genetics, Spinal Cord Injuries physiopathology, Apoptosis drug effects, Calpain antagonists & inhibitors, Cysteine Proteinase Inhibitors pharmacology, Genes, Immediate-Early drug effects, Leucine analogs & derivatives, Leucine pharmacology, Spinal Cord Injuries drug therapy
- Abstract
Upregulation of calpain, a Ca(2+)-activated cysteine protease, has been implicated in apoptosis and tissue degeneration in spinal cord injury (SCI) that over time spreads from the site of injury to the surrounding regions. We examined calpain content and activity, regulation of immediate early genes (IEGs) such as c-jun and c-fos, reactive astrogliosis as the expression of glial fibrillary acidic protein (GFAP), and apoptosis-related features such as caspase-3 mRNA expression and internucleosomal DNA fragmentation in 1-cm long spinal cord segments (S1, distant rostral; S2, adjacent rostral; S3, lesion or injury; S4, adjacent caudal; and S5, distant caudal) following SCI in rats. Calpain content and production of 150 kD calpain-cleaved alpha-fodrin fragment, expression of IEGs, reactive astrogliosis, and apoptotic features were highly increased in the lesion (S3), moderately in adjacent areas (S2 and S4), and slightly in distant areas (S1 and S5) in SCI rats when compared to sham animals. Administration of the calpain-specific inhibitor E-64-d (1 mg/kg) to SCI rats continuously for 24 h inhibited calpain activity and other factors contributing to apoptosis in the lesion and surrounding areas, indicating that calpain played a key role in the pathophysiology of SCI. The results obtained from this animal model of SCI suggest that calpain inhibitor can provide neuroprotection in patients with SCI.
- Published
- 2001
- Full Text
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12. Expression of endothelial and inducible NOS-isoforms is increased in Alzheimer's disease, in APP23 transgenic mice and after experimental brain lesion in rat: evidence for an induction by amyloid pathology.
- Author
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Lüth HJ, Holzer M, Gärtner U, Staufenbiel M, and Arendt T
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid beta-Protein Precursor genetics, Animals, Antibody Specificity, Astrocytes enzymology, Astrocytes pathology, Brain pathology, Brain physiopathology, Brain Injuries genetics, Brain Injuries pathology, Cell Count, Cerebral Cortex enzymology, Cerebral Cortex injuries, Cerebral Cortex pathology, Female, Gene Expression Regulation, Enzymologic physiology, Gliosis enzymology, Gliosis genetics, Gliosis pathology, Humans, Immunohistochemistry, Male, Mice, Mice, Transgenic genetics, Mice, Transgenic metabolism, Plaque, Amyloid genetics, Plaque, Amyloid pathology, Protein Isoforms genetics, Protein Isoforms metabolism, Up-Regulation genetics, Alzheimer Disease enzymology, Amyloid beta-Protein Precursor metabolism, Brain enzymology, Brain Injuries enzymology, Nitric Oxide Synthase metabolism, Plaque, Amyloid metabolism, Promoter Regions, Genetic physiology
- Abstract
The nitric oxide-synthesizing enzyme nitric oxide synthase (NOS) is present in the mammalian brain in three different isoforms, two constitutive enzymes (i.e., neuronal, nNOS, and endothelial eNOS) and one inducible enzyme (iNOS). All three isoforms are aberrantly expressed in Alzheimer's disease giving rise to elevated levels of nitric oxide apparently involved in the pathogenesis of this disease by various different mechanisms including oxidative stress and activation of intracellular signalling mechanisms. It still is a matter of debate, however, whether the abnormal expression of NOS isoforms has some primary importance in the pathogenetic chain and might thus be a potential therapeutic target or only reflects a secondary effect that occurs at more advanced stages of the disease process. To tackle this question, we analysed the expression of both eNOS and iNOS in patients with sporadic AD, in transgenic mice expressing human amyloid precursor protein (APP) with the Swedish double mutation under control of the Thy1 promotor (APP23 mice), and after electrolytic cortical lesion in rat, an experimental paradigm associated with elevated expression of APP. In all three conditions, an astrocytosis was induced accompanied by a strong increase of both iNOS and eNOS. Both NOS isoforms were frequently though not always colocalized. Thus, based on the expression pattern of NOS isoforms three types of astrocytes, expressing only one of the two isoforms or both together could be distinguished. In both AD and transgenic mice eNOS-expressing astrocytes exceeded iNOS-expressing astrocytes in number. Astrocytes with elevated levels of iNOS or eNOS were constantly seen in direct association with Abeta-deposits in AD and transgenic mice and were found in the vicinity of the lesion site in the rat cortex. The results of the present study show that expression of both iNOS and eNOS is increased in activated astrocytes under experimental conditions associated with elevated expression of APP (electrolytic brain lesion) or Abeta-deposition (APP23 transgenic mice). Therefore, it is suggested that altered expression of these NOS isoforms being part of AD pathology is secondary to the amyloid pathology and might not be primarily involved in the pathogenetic chain though it might contribute to the maintenance, self-perpetuation and progression of the neurodegenerative process.
- Published
- 2001
- Full Text
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13. Regional and temporal progression of reactive astrocytosis in the brain of the myelin mutant taiep rat.
- Author
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Leon Chavez BA, Guevara J, Galindo S, Luna J, Ugarte A, Villegas O, Mena R, Eguibar JR, and Martinez-Fong D
- Subjects
- Animals, Astrocytes chemistry, Astrocytes pathology, Ataxia genetics, Biomarkers, Demyelinating Diseases pathology, Disease Progression, Endoplasmic Reticulum, Smooth pathology, Enzyme-Linked Immunosorbent Assay, Epilepsy, Reflex genetics, Fluorescent Antibody Technique, Indirect, Glial Fibrillary Acidic Protein analysis, Gliosis pathology, Hypertrophy, Microtubules pathology, Rats, Rats, Mutant Strains, Rats, Sprague-Dawley, Seizures genetics, Tremor genetics, Brain pathology, Demyelinating Diseases genetics, Gliosis genetics
- Abstract
Reactive astrocytosis in taiep rats was shown by glial fibrillary acidic protein (GFAP) immunoreactivity measured by means of enzyme-linked immunosorbent assay and indirect immunofluorescence. Increased GFAP immunoreactivity was first observed in the brainstem of 15-day-old taiep rats and was widespread throughout all brain regions at 6 months of age. Characteristically, astrocytes were hypertrophic and displayed strong GFAP fluorescence. The pattern of these reactive cells may correlate with the process of dysmyelination in the taiep rat.
- Published
- 2001
- Full Text
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14. Region-specific astrogliosis in brains of mice heterozygous for mutations in the neurofibromatosis type 1 (Nf1) tumor suppressor.
- Author
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Rizvi TA, Akunuru S, de Courten-Myers G, Switzer RC 3rd, Nordlund ML, and Ratner N
- Subjects
- Animals, Astrocytes metabolism, Brain metabolism, Cerebellum metabolism, Cerebellum pathology, Cerebral Cortex metabolism, Cerebral Cortex pathology, Glial Fibrillary Acidic Protein biosynthesis, Gliosis genetics, Gliosis metabolism, Heterozygote, Hippocampus metabolism, Hippocampus pathology, Male, Mice, Mice, Inbred C57BL, Mice, Neurologic Mutants, Mutation, Nerve Degeneration metabolism, Nerve Degeneration pathology, Nucleus Accumbens metabolism, Nucleus Accumbens pathology, Periaqueductal Gray metabolism, Periaqueductal Gray pathology, Thalamus metabolism, Thalamus pathology, Tubulin metabolism, Brain pathology, Disease Models, Animal, Genes, Neurofibromatosis 1 genetics, Gliosis pathology
- Abstract
Brains from human neurofibromatosis type 1 (NF1) patients show increased expression of glial fibrillary acidic protein (GFAP), consistent with activation of astrocytes (M.L. Nordlund, T.A. Rizvi, C.I. Brannan, N. Ratner, Neurofibromin expression and astrogliosis in neurofibromatosis (type 1) brains, J. Neuropathol. Exp. Neurology 54 (1995) 588-600). We analyzed brains from transgenic mice in which the Nf1 gene was targeted by homologous recombination. We show here that, in all heterozygous mice analyzed, there are increased numbers of astrocytes expressing high levels of GFAP in medial regions of the periaqueductal gray and in the nucleus accumbens. More subtle, but significant, changes in the number of GFAP positive astrocytes were observed in the hippocampus in 60% of mutant mice analyzed. Astrocytes with elevated GFAP were present at 1 month, 2 months, 6 months and 12 months after birth. Most brain regions, including the cerebellum, basal ganglia, cerebral cortex, hypothalamus, thalamus, cortical amygdaloid area, and white matter tracts did not show any gliotic changes. No evidence of degenerating neurons was found using de Olmos' cupric silver stain. We conclude that Nf1/nf1 mice provide a model to study astrogliosis associated with neurofibromatosis type 1., (Copyright 1999 Elsevier Science B.V.)
- Published
- 1999
- Full Text
- View/download PDF
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