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  • 1
    Language: English
    In: Neuron (Cambridge, Mass.), 2013-05-22, Vol.78 (4), p.575-577
    Description: In this issue of Neuron, Griciuc et al. (2013) investigate the Alzheimer’s disease risk gene, CD33. AD brains have increased CD33 and CD33-positive microglia. Mice lacking CD33 have less AD pathology suggesting a role of microglia for Aβ clearance and development of future therapies.
    Subject(s): Sialic Acid Binding Ig-like Lectin 3 - genetics ; Microglia - metabolism ; Animals ; Alzheimer Disease - genetics ; Humans ; Amyloid beta-Peptides - metabolism ; Alzheimer's disease ; Amyloidosis ; Amyloid beta-protein ; Index Medicus
    ISSN: 0896-6273
    E-ISSN: 1097-4199
    Source: Backfile Package - All of Back Files EBS [ALLOFBCKF]
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 2
    Language: English
    In: Journal of neuroinflammation, 2012-01-31, Vol.9 (1), p.27-27
    Description: Background: Most of the known functions of microglia, including neurotoxic and neuroprotective properties, are attributed to morphologically-activated microglia. Resting, ramified microglia are suggested to primarily monitor their environment including synapses. Here, we show an active protective role of ramified microglia in excitotoxicity-induced neurodegeneration. Methods: Mouse organotypic hippocampal slice cultures were treated with N-methyl-D-aspartic acid (NMDA) to induce excitotoxic neuronal cell death. This procedure was performed in slices containing resting microglia or slices that were chemically or genetically depleted of their endogenous microglia. Results: Treatment of mouse organotypic hippocampal slice cultures with 10-50 mu M N-methyl-D-aspartic acid (NMDA) induced region-specific excitotoxic neuronal cell death with CA1 neurons being most vulnerable, whereas CA3 and DG neurons were affected less. Ablation of ramified microglia severely enhanced NMDA-induced neuronal cell death in the CA3 and DG region rendering them almost as sensitive as CA1 neurons. Replenishment of microglia-free slices with microglia restored the original resistance of CA3 and DG neurons towards NMDA. Conclusions: Our data strongly suggest that ramified microglia not only screen their microenvironment but additionally protect hippocampal neurons under pathological conditions. Morphological activation of ramified microglia is thus not required to influence neuronal survival.
    Subject(s): KAINATE NEUROTOXICITY ; Organotypic hippocampal slice cultures ; UMCG Approved ; Microglia ; CELL-DEATH ; FACTOR-ALPHA ; SLICE CULTURES ; Ganciclovir ; TUMOR-NECROSIS-FACTOR ; Excitotoxicity ; NEURONAL DEATH ; NMDA ; NITRIC-OXIDE ; RAT HIPPOCAMPUS ; DENTATE GYRUS ; Clodronate ; NERVOUS-TISSUE ; Microglia - cytology ; Microglia - drug effects ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurotoxins - toxicity ; Phosphopyruvate Hydratase - metabolism ; Hippocampus - drug effects ; Glial Fibrillary Acidic Protein - metabolism ; Hippocampus - cytology ; Nerve Degeneration - pathology ; Dose-Response Relationship, Drug ; CD11b Antigen - genetics ; Animals ; Microglia - physiology ; Clodronic Acid - toxicity ; Mice ; Cell Death - drug effects ; Neurons - drug effects ; Organ Culture Techniques ; N-Methylaspartate - toxicity ; Nerve Degeneration - therapy ; Prevention ; Methyl aspartate ; Complications and side effects ; Cell culture ; Nervous system ; Degeneration ; Research ; Methods ; Index Medicus
    ISSN: 1742-2094
    E-ISSN: 1742-2094
    Source: Directory of Open Access Journals
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 3
    Language: English
    In: Nature reviews. Neuroscience, 2015-06, Vol.16 (6), p.358-372
    Description: The past two decades of research into the pathogenesis of Alzheimer disease (AD) have been driven largely by the amyloid hypothesis; the neuroinflammation that is associated with AD has been assumed to be merely a response to pathophysiological events. However, new data from preclinical and clinical studies have established that immune system-mediated actions in fact contribute to and drive AD pathogenesis. These insights have suggested both novel and well-defined potential therapeutic targets for AD, including microglia and several cytokines. In addition, as inflammation in AD primarily concerns the innate immune system - unlike in 'typical' neuroinflammatory diseases such as multiple sclerosis and encephalitides - the concept of neuroinflammation in AD may need refinement.
    Subject(s): Inflammation - pathology ; Inflammation - immunology ; Animals ; Alzheimer Disease - immunology ; Humans ; Alzheimer Disease - pathology ; Care and treatment ; Analysis ; Development and progression ; Inflammation ; Research ; Alzheimer's disease ; Health aspects ; Immune system ; Dementia ; Index Medicus
    ISSN: 1471-003X
    E-ISSN: 1471-0048
    Source: Nature Reviews
    Source: Academic Search Ultimate
    Source: Nature Journals Online
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  • 4
    Language: English
    In: International journal of molecular sciences, 2020-06-11, Vol.21 (11), p.4179
    Description: Glioblastoma (GBM) present with an abundant and aberrant tumor neo-vasculature. While rapid growth of solid tumors depends on the initiation of tumor angiogenesis, GBM also progress by infiltrative growth and vascular co-option. The angiogenic factor apelin ( ) and its receptor ( ) are upregulated in GBM patient samples as compared to normal brain tissue. Here, we studied the role of apelin/APLNR signaling in GBM angiogenesis and growth. By functional analysis of apelin in orthotopic GBM mouse models, we found that apelin/APLNR signaling is required for in vivo tumor angiogenesis. Knockdown of tumor cell-derived massively reduced the tumor vasculature. Additional loss of the apelin signal in endothelial tip cells using the -knockout (KO) mouse led to a further reduction of GBM angiogenesis. Direct infusion of the bioactive peptide apelin-13 rescued the vascular loss-of-function phenotype specifically. In addition, depletion massively reduced angiogenesis-dependent tumor growth. Consequently, survival of GBM-bearing mice was significantly increased when expression was missing in the brain tumor microenvironment. Thus, we suggest that targeting vascular apelin may serve as an alternative strategy for anti-angiogenesis in GBM.
    Subject(s): Brain Neoplasms - diagnostic imaging ; Humans ; Gene Expression Regulation, Neoplastic ; Tumor Microenvironment ; Brain Neoplasms - blood supply ; Brain Neoplasms - drug therapy ; Apelin - genetics ; Mice, Knockout ; Neoplasms, Experimental - diagnostic imaging ; Neovascularization, Pathologic - pathology ; Xenograft Model Antitumor Assays ; Magnetic Resonance Imaging ; Apelin - metabolism ; Glioblastoma - diagnostic imaging ; Animals ; Intercellular Signaling Peptides and Proteins - pharmacology ; Cell Line, Tumor ; Neovascularization, Pathologic - metabolism ; Brain Neoplasms - mortality ; Neoplasms, Experimental - mortality ; Glioblastoma - drug therapy ; Glioblastoma - blood supply ; Glioblastoma - mortality ; Neoplasms, Experimental - blood supply ; Index Medicus ; APLNR ; Apelin-13 ; glioblastoma ; GBM angiogenesis ; APLN
    ISSN: 1422-0067
    ISSN: 1661-6596
    E-ISSN: 1422-0067
    Source: Directory of Open Access Journals
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 5
    Language: English
    In: Scientific reports, 2021-02-19, Vol.11 (1), p.4263-4263
    Description: Infection by the new corona virus strain SARS-CoV-2 and its related syndrome COVID-19 has been associated with more than two million deaths worldwide. Patients of higher age and with preexisting chronic health conditions are at an increased risk of fatal disease outcome. However, detailed information on causes of death and the contribution of pre-existing health conditions to death yet is missing, which can be reliably established by autopsy only. We performed full body autopsies on 26 patients that had died after SARS-CoV-2 infection and COVID-19 at the Charité University Hospital Berlin, Germany, or at associated teaching hospitals. We systematically evaluated causes of death and pre-existing health conditions. Additionally, clinical records and death certificates were evaluated. We report findings on causes of death and comorbidities of 26 decedents that had clinically presented with severe COVID-19. We found that septic shock and multi organ failure was the most common immediate cause of death, often due to suppurative pulmonary infection. Respiratory failure due to diffuse alveolar damage presented as immediate cause of death in fewer cases. Several comorbidities, such as hypertension, ischemic heart disease, and obesity were present in the vast majority of patients. Our findings reveal that causes of death were directly related to COVID-19 in the majority of decedents, while they appear not to be an immediate result of preexisting health conditions and comorbidities. We therefore suggest that the majority of patients had died of COVID-19 with only contributory implications of preexisting health conditions to the mechanism of death.
    Subject(s): Multiple Organ Failure - mortality ; Prospective Studies ; Humans ; Middle Aged ; Male ; Berlin - epidemiology ; Shock, Septic - virology ; Cause of Death ; Hospitals, Teaching - statistics & numerical data ; Autopsy ; COVID-19 - complications ; Aged, 80 and over ; Adult ; Female ; Hypertension - epidemiology ; Myocardial Ischemia - epidemiology ; COVID-19 - virology ; Multiple Organ Failure - virology ; Hospital Mortality ; Comorbidity ; COVID-19 - mortality ; Shock, Septic - mortality ; COVID-19 - therapy ; SARS-CoV-2 - isolation & purification ; Obesity - epidemiology ; Aged ; Severe acute respiratory syndrome coronavirus 2 ; COVID-19 ; Ischemia ; Septic shock ; Death ; Infections ; Coronaviruses ; Alveoli ; Heart diseases ; Patients ; Coronary artery disease ; Index Medicus
    ISSN: 2045-2322
    E-ISSN: 2045-2322
    Source: Nature Open Access
    Source: Directory of Open Access Journals
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 6
    Language: English
    In: Science (American Association for the Advancement of Science), 2001-10-05, Vol.294 (5540), p.178-182
    Description: Variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy are initiated by extracerebral exposure to prions. Although prion transmission from extracerebral sites to the brain represents a potential target for prophylaxis, attempts at vaccination have been limited by the poor immunogenicity of prion proteins. To circumvent this, we expressed an anti-prion protein (anti-PrP) μ chain in Prnp mice. Transgenic mice developed sustained anti-PrP titers, which were not suppressed by introduction of Prnp alleles. Transgene expression prevented pathogenesis of prions introduced by intraperitoneal injection in the spleen and brain. Expression of endogenous PrP (PrP ) in the spleen and brain was unaffected, suggesting that immunity was responsible for protection. This indicates the feasibility of immunological inhibition of prion disease in vivo.
    Subject(s): Spleen ; T lymphocytes ; B lymphocytes ; Transgenic animals ; Prions ; Antibodies ; Prion diseases ; Reports ; Mice ; Transgenes ; Blood ; Neurology ; Biological and medical sciences ; Medical sciences ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Prion Proteins ; Prions - genetics ; Spleen - immunology ; PrPSc Proteins - immunology ; PrPSc Proteins - analysis ; Immunoglobulin M - immunology ; Prions - immunology ; Flow Cytometry ; Antibodies - immunology ; PrPC Proteins - genetics ; Amyloid - genetics ; Protein Precursors - genetics ; Scrapie - prevention & control ; Enzyme-Linked Immunosorbent Assay ; Immunoglobulin mu-Chains - immunology ; Cell Separation ; Mice, Inbred C57BL ; Mice, Transgenic ; Blotting, Western ; Spleen - chemistry ; Animals ; B-Lymphocytes - immunology ; Immunoglobulin M - blood ; Antibodies - blood ; Brain Chemistry ; Immunoglobulin mu-Chains - blood ; Prevention ; Vaccination ; Creutzfeldt-Jakob disease ; Nerve degeneration ; Nervous system ; Degeneration ; Biochemistry ; Research ; Bovine spongiform encephalopathy ; Index Medicus
    ISSN: 0036-8075
    E-ISSN: 1095-9203
    Source: Single Journals
    Source: Academic Search Ultimate
    Source: EBSCOhost EJS
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  • 7
    Article
    Article
    2013
    ISSN: 0001-6322 
    Language: English
    In: Acta neuropathologica, 2013-10, Vol.126 (4), p.461-477
    Description: The identification of microglia-associated, neurological disease-causing mutations in patients, combined with studies in mouse models has highlighted microglia, the brain’s intrinsic myeloid cells, as key modulators of pathogenesis and disease progression in neurodegenerative diseases. In Alzheimer’s disease (AD) in particular, the activation and accumulation of microglial cells around β-Amyloid (Aβ) plaques has long been described and is believed to result in chronic neuroinflammation—a term that, despite being commonly used, lacks a precise definition. This seemingly directed response of microglia to amyloid deposits conflicts with the fact that the increasing buildup of Aβ plaques is not inhibited by these cells during disease progression. While recent evidence suggests that microglia lose their intrinsic beneficial function during the course of AD and may even acquire a “toxic” phenotype over time, Aβ may also simply not be an appropriate trigger to induce phagocytosis and degradation by microglia in vivo. As recent experimental evidence has indicated the importance of the microglia in AD pathogenesis, future efforts aimed at tackling this disease via utilization or modulation of microglia or factors therefrom appear to be an exciting and challenging research front.
    Subject(s): Pathology ; Neurosciences ; Medicine & Public Health ; Alzheimer’s disease ; Cellular senescence ; Activation ; Phagocytosis ; Microglia ; Macrophage Activation - physiology ; Microglia - metabolism ; Humans ; Myeloid Cells - physiology ; Cellular Senescence - physiology ; Alzheimer Disease - pathology ; Phenotype ; Animals ; Microglia - immunology ; Microglia - physiology ; Alzheimer Vaccines - therapeutic use ; Alzheimer Disease - metabolism ; Amyloid beta-Peptides - immunology ; Alzheimer Disease - genetics ; Alzheimer Disease - immunology ; Development and progression ; Alzheimer's disease ; Amyloid beta-protein ; Index Medicus
    ISSN: 0001-6322
    E-ISSN: 1432-0533
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 8
    Language: English
    In: Acta neuropathologica communications, 2019-06-05, Vol.7 (1), p.89-89
    Description: Methylation of the O(6)-Methylguanine-DNA methyltransferase (MGMT) promoter is predictive for treatment response in glioblastoma patients. However, precise predictive cutoff values to distinguish "MGMT methylated" from "MGMT unmethylated" patients remain highly debated in terms of pyrosequencing (PSQ) analysis. We retrospectively analyzed a clinically and molecularly very well-characterized cohort of 111 IDH wildtype glioblastoma patients, who underwent gross total tumor resection and received standard Stupp treatment. Detailed clinical parameters were obtained. Predictive cutoff values for MGMT promoter methylation were determined using ROC curve analysis and survival curve comparison using Log-rank (Mantel-Cox) test. MGMT status was analyzed using pyrosequencing (PSQ), semi-quantitative methylation specific PCR (sqMSP) and direct bisulfite sequencing (dBiSeq). Highly methylated (〉 20%) MGMT correlated with significantly improved progression-free survival (PFS) and overall survival (OS) in our cohort. Median PFS was 7.2 months in the unmethylated group (UM, 〈 10% mean methylation), 10.4 months in the low methylated group (LM, 10-20% mean methylation) and 19.83 months in the highly methylated group (HM, 〉 20% mean methylation). Median OS was 13.4 months for UM, 17.9 months for LM and 29.93 months for HM. Within the LM group, correlation of PSQ and sqMSP or dBiSeq was only conclusive in 51.5% of our cases. ROC curve analysis revealed superior test precision for survival if additional sqMSP results were considered (AUC = 0.76) compared to PSQ (cutoff 10%) alone (AUC = 0.67). We therefore challenge the widely used, strict PSQ cutoff at 10% which might not fully reflect the clinical response to alkylating agents and suggest applying a second method for MGMT testing (e.g. MSP) to confirm PSQ results for patients with LM MGMT levels if therapeutically relevant.
    Subject(s): Sulfites ; Nucleotide sequencing ; Methylation ; Glioblastoma multiforme ; DNA sequencing ; Medical research ; Decision making ; Brain cancer ; Oncology ; Radiation therapy ; Patients ; Ethics ; Medical prognosis ; DNA methylation ; Biomarkers ; Software ; Deoxyribonucleic acid--DNA ; Tumors ; Index Medicus ; Methylation specific PCR (MSP) ; O-Methylguanine-DNA methyltransferase (MGMT) ; Pyrosequencing (PSQ) ; Temozolomide (TMZ) ; IDH (isocitrate dehydrogenase) ; Glioblastoma
    ISSN: 2051-5960
    E-ISSN: 2051-5960
    Source: Directory of Open Access Journals
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
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  • 9
    Language: English
    In: Acta neuropathologica communications, 2017-06-24, Vol.5 (1), p.52-52
    Description: The immunoproteasome (iP) represents a specialized type of proteasomes, which plays an important role in the clearance of oxidant-damaged proteins under inflammatory and pathological conditions determining the outcome of various diseases. In Alzheimer's disease (AD)-like APPPS1 mice A[beta]-deposition is paralleled by iP upregulation, most likely mediated through type I interferon induction. To define the impact of increased iP expression we crossed APPPS1 mice with mice deficient in the iP subunit LMP7 resulting in impaired iP function. While LMP7 deficient APPPS1 mice showed no major change in cerebral A[beta]-pathology, we observed an altered cytokine response in microglia isolated from LMP7 deficient APPPS1 mice compared to LMP7 expressing APPPS1 control mice. The altered microglial cytokine profile upon iP deficiency in the presence of extracellular A[beta]-pathology was associated with an improvement of A[beta]-associated cognitive deficits typically present in APPPS1 mice. Our findings suggest a role for iP in the regulation of the innate immune response towards extracellular A[beta]-pathology and indicate that inhibition of iP function can modulate the cognitive phenotype upon overexpression of A[beta].
    Subject(s): Advertising executives ; Interferon ; Biological response modifiers ; Alzheimer's disease ; Proteins ; Brain ; Pathology ; Disease ; Cytokines ; Neuropathology ; Rodents ; Cell cycle ; Homeostasis ; Mutation ; Gene expression ; Animal cognition ; Index Medicus ; Inflammation ; Research ; Alzheimer’s disease ; Immunoproteasome ; Proteasome ; Microglia
    ISSN: 2051-5960
    E-ISSN: 2051-5960
    Source: Directory of Open Access Journals
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
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  • 10
    Language: English
    In: Acta neuropathologica communications, 2019-07-04, Vol.7 (1), p.106-106
    Description: [...]experiments undertaken in mice demonstrate that overexpression of interferon in the CNS results in neuropathology reminiscent of that seen in certain type I interferonopathies [1, 10]. The escalating spiral of white matter damage might be initiated by type I IFN that is induced in microglia via stimulator of interferon genes (STING), and this IFN likely influences the microglial phenotype in an autocrine and paracrine fashion [13]. Akwa Y, Hassett DE, Eloranta ML, Sandberg K, Masliah E, Powell H, Whitton JL, Bloom FE, Campbell IL (1998) Transgenic expression of IFN-alpha in the central nervous system of mice protects against lethal neurotropic viral infection but induces inflammation and neurodegeneration. Cell Death Dis 7:e2444. https://doi.org/10.1038/cddis.2016.326 View ArticlePubMedPubMed CentralGoogle Scholar Kavanagh D, McGlasson S, Jury A, Williams J, Scolding N, Bellamy C, Gunther C, Ritchie D, Gale DP, Kanwar YS et al (2016) Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature.
    Subject(s): Type I interferon ; Microgliosis ; Usp18 ; Behavior ; Magnet resonance spectroscopy ; White matter ; Corpus callosum ; Phagocytosis ; Microglia ; Biological response modifiers ; Proteases ; Interferon ; Brain ; Neurosciences ; Young adults ; Disease ; Histology ; Mutation ; Age ; Index Medicus ; Letter to the Editor
    ISSN: 2051-5960
    E-ISSN: 2051-5960
    Source: Directory of Open Access Journals
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
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