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https://www.readbyqxmd.com/read/28381303/retention-of-normal-glia-function-by-an-isoform-selective-protein-kinase-inhibitor-drug-candidate-that-modulates-cytokine-production-and-cognitive-outcomes
#1
Zhengqiu Zhou, Adam D Bachstetter, Claudia B Späni, Saktimayee M Roy, D Martin Watterson, Linda J Van Eldik
BACKGROUND: Brain p38α mitogen-activated protein kinase (MAPK), a potential therapeutic target for cognitive dysfunction based on the neuroinflammation-synaptic dysfunction cycle of pathophysiology progression, offers an innovative pharmacological strategy via inhibiting the same activated target in both glia and neurons, thereby enhancing the possibility for efficacy. The highly selective, brain-penetrant p38αMAPK inhibitor MW150 attenuates cognitive dysfunction in two distinct Alzheimer's disease (AD)-relevant models and avoids the problems encountered with previous mixed-kinase inhibitor drug candidates...
April 5, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28361437/effect-of-preventive-and-curative-fingolimod-treatment-regimens-on-microglia-activation-and-disease-progression-in-a-rat-model-of-multiple-sclerosis
#2
David Vállez García, Janine Doorduin, Daniele de Paula Faria, Rudi A J O Dierckx, Erik F J de Vries
Fingolimod was the first oral drug approved for multiple sclerosis treatment. Its principal mechanism of action is blocking of lymphocyte trafficking. In addition, recent studies have shown its capability to diminish microglia activation. The effect of preventive and curative fingolimod treatment on the time-course of neuroinflammation was investigated in the experimental autoimmune encephalomyelitis rat model for multiple sclerosis. Neuroinflammatory progression was followed in Dark Agouti female rats after immunization...
March 30, 2017: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/28358926/genetically-engineered-rat-gliomas-pdgf-driven-tumor-initiation-and-progression-in-tv-a-transgenic-rats-recreate-key-features-of-human-brain-cancer
#3
Nina P Connolly, Jesse A Stokum, Craig S Schneider, Tatsuya Ozawa, Su Xu, Rebeca Galisteo, Rudolph J Castellani, Anthony J Kim, J Marc Simard, Jeffrey A Winkles, Eric C Holland, Graeme F Woodworth
Previously rodent preclinical research in gliomas frequently involved implantation of cell lines such as C6 and 9L into the rat brain. More recently, mouse models have taken over, the genetic manipulability of the mouse allowing the creation of genetically accurate models outweighed the disadvantage of its smaller brain size that limited time allowed for tumor progression. Here we illustrate a method that allows glioma formation in the rat using the replication competent avian-like sarcoma (RCAS) virus / tumor virus receptor-A (tv-a) transgenic system of post-natal cell type-specific gene transfer...
2017: PloS One
https://www.readbyqxmd.com/read/28242869/in-vivo-imaging-of-translocator-protein-a-marker-of-activated-microglia-in-alcohol-dependence
#4
A T Hillmer, C M Sandiego, J Hannestad, G A Angarita, A Kumar, E M McGovern, Y Huang, K C O'Connor, R E Carson, S S O'Malley, K P Cosgrove
Neuroinflammation may be a critical component of the neurobiology of alcohol use disorders, yet the exact nature of this relationship is not well understood. This work compared the brain and peripheral immune profile of alcohol-dependent subjects and controls. Brain levels of 18-kDa translocator protein (TSPO), a marker of microglial activation and neuroinflammation, were measured with [(11)C]PBR28 positron emission tomography imaging in 15 healthy controls and 15 alcohol-dependent subjects. Alcohol-dependent subjects were imaged 1-4 days (n=14) or 24 days (n=1) after their last drink...
February 28, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28122877/an-early-and-late-peak-in-microglial-activation-in-alzheimer-s-disease-trajectory
#5
Zhen Fan, David J Brooks, Aren Okello, Paul Edison
Amyloid-β deposition, neuroinflammation and tau tangle formation all play a significant role in Alzheimer's disease. We hypothesized that there is microglial activation early on in Alzheimer's disease trajectory, where in the initial phase, microglia may be trying to repair the damage, while later on in the disease these microglia could be ineffective and produce proinflammatory cytokines leading to progressive neuronal damage. In this longitudinal study, we have evaluated the temporal profile of microglial activation and its relationship between fibrillar amyloid load at baseline and follow-up in subjects with mild cognitive impairment, and this was compared with subjects with Alzheimer's disease...
March 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28111081/phosphatidylserine-exposure-controls-viral-innate-immune-responses-by-microglia
#6
Yusuf Tufail, Daniela Cook, Lawrence Fourgeaud, Colin J Powers, Katharina Merten, Charles L Clark, Elizabeth Hoffman, Alexander Ngo, Kohei J Sekiguchi, Clodagh C O'Shea, Greg Lemke, Axel Nimmerjahn
Microglia are the intrinsic immune sentinels of the central nervous system. Their activation restricts tissue injury and pathogen spread, but in some settings, including viral infection, this response can contribute to cell death and disease. Identifying mechanisms that control microglial responses is therefore an important objective. Using replication-incompetent adenovirus 5 (Ad5)-based vectors as a model, we investigated the mechanisms through which microglia recognize and respond to viral uptake. Transgenic, immunohistochemical, molecular-genetic, and fluorescence imaging approaches revealed that phosphatidylserine (PtdSer) exposure on the outer leaflet of transduced cells triggers their engulfment by microglia through TAM receptor-dependent mechanisms...
February 8, 2017: Neuron
https://www.readbyqxmd.com/read/28101527/regulation-of-physical-microglia-neuron-interactions-by-fractalkine-signaling-after-status-epilepticus
#7
Ukpong B Eyo, Jiyun Peng, Madhuvika Murugan, Mingshu Mo, Almin Lalani, Ping Xie, Pingyi Xu, David J Margolis, Long-Jun Wu
Microglia, the resident immune cells of the brain, perform elaborate surveillance in which they physically interact with neuronal elements. A novel form of microglia-neuron interaction named microglial process convergence (MPC) toward neuronal axons and dendrites has recently been described. However, the molecular regulators and pathological relevance of MPC have not been explored. Here, using high-resolution two-photon imaging in vivo and ex vivo, we observed a dramatic increase in MPCs after kainic acid- or pilocarpine-induced experimental seizures that was reconstituted after glutamate treatment in slices from mice...
November 2016: ENeuro
https://www.readbyqxmd.com/read/28093569/translational-evaluation-of-translocator-protein-as-a-marker-of-neuroinflammation-in-schizophrenia
#8
T Notter, J M Coughlin, T Gschwind, U Weber-Stadlbauer, Y Wang, M Kassiou, A C Vernon, D Benke, M G Pomper, A Sawa, U Meyer
Positron emission tomography (PET) imaging with radiotracers that target translocator protein 18 kDa (TSPO) has become a popular approach to assess putative neuroinflammatory processes and associated microglia activation in psychotic illnesses. It remains unclear, however, whether TSPO imaging can accurately capture low-grade inflammatory processes such as those present in schizophrenia and related disorders. Therefore, we evaluated the validity of TSPO as a disease-relevant marker of inflammation using a translational approach, which combined neurodevelopmental and neurodegenerative mouse models with PET imaging in patients with recent-onset schizophrenia and matched controls...
January 17, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28063058/microglial-activation-by-genetically-targeted-conditional-neuronal-ablation-in-the-zebrafish
#9
Nynke Oosterhof, Laura E Kuil, Tjakko J van Ham
In neurodegenerative diseases activation of immune cells is thought to play a major role. Microglia are the main immune cells of the central nervous system. When encountering disease related stimuli microglia adopt an activated phenotype that typically includes a rounded morphology. The exact role of microglia or other potentially infiltrating myeloid cells in different brain diseases is not fully understood. In this chapter we present techniques in zebrafish to induce degeneration of neurons, to activate the microglia, and to study activation phenotypes by immunohistochemistry and in vivo by fluorescence microscopic imaging...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27960090/critical-role-of-the-cxcl10-c-x-c-chemokine-receptor-3-axis-in-promoting-leukocyte-recruitment-and-neuronal-injury-during-traumatic-optic-neuropathy-induced-by-optic-nerve-crush
#10
Yonju Ha, Hua Liu, Shuang Zhu, Panpan Yi, Wei Liu, Jared Nathanson, Rakez Kayed, Bradford Loucas, Jiaren Sun, Laura J Frishman, Massoud Motamedi, Wenbo Zhang
Traumatic optic neuropathy (TON) is an acute injury of the optic nerve secondary to trauma. Loss of retinal ganglion cells (RGCs) is a key pathological process in TON, yet mechanisms responsible for RGC death remain unclear. In a mouse model of TON, real-time noninvasive imaging revealed a dramatic increase in leukocyte rolling and adhesion in veins near the optic nerve (ON) head at 9 hours after ON injury. Although RGC dysfunction and loss were not detected at 24 hours after injury, massive leukocyte infiltration was observed in the superficial retina...
February 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/27932309/binge-alcohol-alters-exercise-driven-neuroplasticity
#11
Emily A Barton, Yanbin Lu, Murad Megjhani, Mark E Maynard, Prathamesh M Kulkarni, Badrinath Roysam, J Leigh Leasure
Exercise is increasingly being used as a treatment for alcohol use disorders (AUD), but the interactive effects of alcohol and exercise on the brain remain largely unexplored. Alcohol damages the brain, in part by altering glial functioning. In contrast, exercise promotes glial health and plasticity. In the present study, we investigated whether binge alcohol would attenuate the effects of subsequent exercise on glia. We focused on the medial prefrontal cortex (mPFC), an alcohol-vulnerable region that also undergoes neuroplastic changes in response to exercise...
February 20, 2017: Neuroscience
https://www.readbyqxmd.com/read/27893897/imaging-of-glial-cell-activation-and-white-matter-integrity-in-brains-of-active-and-recently-retired-national-football-league-players
#12
Jennifer M Coughlin, Yuchuan Wang, Il Minn, Nicholas Bienko, Emily B Ambinder, Xin Xu, Matthew E Peters, John W Dougherty, Melin Vranesic, Soo Min Koo, Hye-Hyun Ahn, Merton Lee, Chris Cottrell, Haris I Sair, Akira Sawa, Cynthia A Munro, Christopher J Nowinski, Robert F Dannals, Constantine G Lyketsos, Michael Kassiou, Gwenn Smith, Brian Caffo, Susumu Mori, Tomas R Guilarte, Martin G Pomper
Importance: Microglia, the resident immune cells of the central nervous system, play an important role in the brain's response to injury and neurodegenerative processes. It has been proposed that prolonged microglial activation occurs after single and repeated traumatic brain injury, possibly through sports-related concussive and subconcussive injuries. Limited in vivo brain imaging studies months to years after individuals experience a single moderate to severe traumatic brain injury suggest widespread persistent microglial activation, but there has been little study of persistent glial cell activity in brains of athletes with sports-related traumatic brain injury...
January 1, 2017: JAMA Neurology
https://www.readbyqxmd.com/read/27875002/superparamagnetic-nanoparticle-enhanced-mri-of-alzheimer-s-disease-plaques-and-activated-microglia-in-3x-transgenic-mouse-brains-contrast-optimization
#13
Marissa A Tafoya, Saaussan Madi, Laurel O Sillerud
PURPOSE: To optimize magnetic resonance imaging (MRI) of antibody-conjugated superparamagnetic nanoparticles for detecting amyloid-β plaques and activated microglia in a 3X transgenic mouse model of Alzheimer's disease. MATERIALS AND METHODS: Ten 3X Tg mice were fed either chow or chow containing 100 ppm resveratrol. Four brains, selected from animals injected with either anti-amyloid targeted superparamagnetic iron oxide nanoparticles, or anti-Iba-1-conjugated FePt-nanoparticles, were excised, fixed with formalin, and placed in Fomblin for ex vivo MRI (11...
November 22, 2016: Journal of Magnetic Resonance Imaging: JMRI
https://www.readbyqxmd.com/read/27815396/quantitative-analysis-of-the-cellular-microenvironment-of-glioblastoma-to-develop-predictive-statistical-models-of-overall-survival
#14
Jessica X Yuan, Fahad F Bafakih, James W Mandell, Bethany J Horton, Jennifer M Munson
Glioblastomas, the most common primary malignant brain tumors, have a distinct tissue microenvironment. Although non-neoplastic cells contribute to glioblastoma progression, very few quantitative studies have shown the effect of tumor microenvironmental influences on patient survival. We examined relationships of the cellular microenvironment, including astrocytes, microglia, oligodendrocytes, and blood vessels, to survival in glioblastoma patients. Using histological staining and quantitative image analyses, we examined the tumor-associated parenchyma of 33 patients and developed statistical models to predict patient outcomes based on the cellular picture of the tumor parenchyma...
December 1, 2016: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/27757989/identification-of-a-conserved-and-acute-neurodegeneration-specific-microglial-transcriptome-in-the-zebrafish
#15
Nynke Oosterhof, Inge R Holtman, Laura E Kuil, Herma C van der Linde, Erik W G M Boddeke, Bart J L Eggen, Tjakko J van Ham
Microglia are brain resident macrophages important for brain development, connectivity, homeostasis and disease. However, it is still largely unclear how microglia functions and their identity are regulated at the molecular level. Although recent transcriptomic studies have identified genes specifically expressed in microglia, the function of most of these genes in microglia is still unknown. Here, we performed RNA sequencing on microglia acutely isolated from healthy and neurodegenerative zebrafish brains...
January 2017: Glia
https://www.readbyqxmd.com/read/27733171/persistent-neuroinflammation-and-cognitive-impairment-in-a-rat-model-of-acute-diisopropylfluorophosphate-intoxication
#16
Brenna M Flannery, Donald A Bruun, Douglas J Rowland, Christopher N Banks, Adam T Austin, David L Kukis, Yonggang Li, Byron D Ford, Daniel J Tancredi, Jill L Silverman, Simon R Cherry, Pamela J Lein
BACKGROUND: Acute intoxication with organophosphorus (OP) cholinesterase inhibitors can trigger convulsions that progress to life-threatening status epilepticus. Survivors face long-term morbidity including mild-to-severe decline in memory. It is posited that neuroinflammation plays a key role in the pathogenesis of OP-induced neuropsychiatric deficits. Rigorous testing of this hypothesis requires preclinical models that recapitulate relevant phenotypic outcomes. Here, we describe a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP) that exhibits persistent neuroinflammation and cognitive impairment...
October 12, 2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27689748/age-related-changes-in-cerebellar-and-hypothalamic-function-accompany-non-microglial-immune-gene-expression-altered-synapse-organization-and-excitatory-amino-acid-neurotransmission-deficits
#17
Stephen J Bonasera, Jyothi Arikkath, Michael D Boska, Tammy R Chaudoin, Nicholas W DeKorver, Evan H Goulding, Traci A Hoke, Vahid Mojtahedzedah, Crystal D Reyelts, Balasrinivasa Sajja, A Katrin Schenk, Laurence H Tecott, Tiffany A Volden
We describe age-related molecular and neuronal changes that disrupt mobility or energy balance based on brain region and genetic background. Compared to young mice, aged C57BL/6 mice exhibit marked locomotor (but not energy balance) impairments. In contrast, aged BALB mice exhibit marked energy balance (but not locomotor) impairments. Age-related changes in cerebellar or hypothalamic gene expression accompany these phenotypes. Aging evokes upregulation of immune pattern recognition receptors and cell adhesion molecules...
September 20, 2016: Aging
https://www.readbyqxmd.com/read/27571884/mri-monitoring-of-monocytes-to-detect-immune-stimulating-treatment-response-in-brain-tumor
#18
Runze Yang, Susobhan Sarkar, Daniel J Korchinski, Ying Wu, V Wee Yong, Jeff F Dunn
Background.: Glioblastoma (GBM) is an aggressive brain cancer with a poor prognosis. The use of immune therapies to treat GBM has become a promising avenue of research. It was shown that amphotericin B (Amp B) can stimulate the innate immune system and suppress the growth of brain tumor initiating cells (BTICs). However, it is not feasible to use histopathology to determine immune activation in patients. We developed an MRI technique that can rapidly detect a therapeutic response in animals treated with drugs that stimulate innate immunity...
March 1, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/27558646/microglia-contact-induces-synapse-formation-in-developing-somatosensory-cortex
#19
Akiko Miyamoto, Hiroaki Wake, Ayako Wendy Ishikawa, Kei Eto, Keisuke Shibata, Hideji Murakoshi, Schuichi Koizumi, Andrew J Moorhouse, Yumiko Yoshimura, Junichi Nabekura
Microglia are the immune cells of the central nervous system that play important roles in brain pathologies. Microglia also help shape neuronal circuits during development, via phagocytosing weak synapses and regulating neurogenesis. Using in vivo multiphoton imaging of layer 2/3 pyramidal neurons in the developing somatosensory cortex, we demonstrate here that microglial contact with dendrites directly induces filopodia formation. This filopodia formation occurs only around postnatal day 8-10, a period of intense synaptogenesis and when microglia have an activated phenotype...
2016: Nature Communications
https://www.readbyqxmd.com/read/27540379/current-evidence-for-a-role-of-the-kynurenine-pathway-of-tryptophan-metabolism-in-multiple-sclerosis
#20
REVIEW
Michael D Lovelace, Bianca Varney, Gayathri Sundaram, Nunzio F Franco, Mei Li Ng, Saparna Pai, Chai K Lim, Gilles J Guillemin, Bruce J Brew
The kynurenine pathway (KP) is the major metabolic pathway of the essential amino acid tryptophan (TRP). Stimulation by inflammatory molecules, such as interferon-γ (IFN-γ), is the trigger for induction of the KP, driving a complex cascade of production of both neuroprotective and neurotoxic metabolites, and in turn, regulation of the immune response and responses of brain cells to the KP metabolites. Consequently, substantial evidence has accumulated over the past couple of decades that dysregulation of the KP and the production of neurotoxic metabolites are associated with many neuroinflammatory and neurodegenerative diseases, including Parkinson's disease, AIDS-related dementia, motor neurone disease, schizophrenia, Huntington's disease, and brain cancers...
2016: Frontiers in Immunology
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