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https://www.readbyqxmd.com/read/29920290/cell-and-stage-specific-localization-of-galectin-3-a-%C3%AE-galactoside-binding-lectin-in-a-mouse-model-of-experimental-autoimmune-encephalomyelitis
#1
Tetsuya Itabashi, Yasunobu Arima, Daisuke Kamimura, Kotaro Higuchi, Yoshio Bando, Hiromi Takahashi-Iwanaga, Masaaki Murakami, Masahiko Watanabe, Toshihiko Iwanaga, Junko Nio-Kobayashi
Multiple sclerosis (MS) is an autoimmune disease in which pathogenic T cells play an important role, and an experimental autoimmune encephalomyelitis (EAE) is used as an animal model of MS. Galectins are β-galactoside-binding lectins and involved in various physiological and pathological events. Among fifteen members of galectins, galectin-1, -8, and -9 play immunosuppressive roles in MS and EAE; however, the role of galectin-3 (gal-3) is complex and controversial. We examined expression of gal-3 in the spinal cord and nerve roots of EAE mice...
June 16, 2018: Neurochemistry International
https://www.readbyqxmd.com/read/29900534/absence-of-infiltrating-peripheral-myeloid-cells-in-the-brains-of-mouse-models-of-lysosomal-storage-disorders
#2
REVIEW
Soo Min Cho, Ayelet Vardi, Nicolas Platt, Anthony H Futerman
Approximately 70 lysosomal storage diseases are currently known, resulting from mutations in genes encoding lysosomal enzymes and membrane proteins. Defects in lysosomal enzymes that hydrolyze sphingolipids have been relatively well studied. Gaucher disease is caused by the loss of activity of glucocerebrosidase, leading to accumulation of glucosylceramide. Gaucher disease exhibits a number of subtypes, with types 2 and 3 showing significant neuropathology. Sandhoff disease results from the defective activity of β-hexosaminidase, leading to accumulation of ganglioside GM2...
June 14, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29873075/caspase-1-activity-influences-juvenile-batten-disease-cln3-pathogenesis
#3
Maria Burkovetskaya, Megan E Bosch, Nikolay Karpuk, Rachel Fallet, Tammy Kielian
Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is an autosomal recessive lysosomal storage disease caused by loss-of-function mutations in CLN3. Symptoms appear between 5-10 years of age, beginning with blindness and seizures, followed by progressive cognitive and motor decline, and premature death. Glial activation and impaired neuronal activity are early signs of pathology in the Cln3Δex7/8 mouse model of JNCL, whereas neuron death occurs much later in the disease process. We previously reported that Cln3Δex7/8 microglia are primed towards a pro-inflammatory phenotype typified by exaggerated caspase-1 inflammasome activation and here we extend those findings to demonstrate heightened caspase activity in the Cln3Δex7/8 mouse brain...
June 5, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29872438/experimental-stroke-differentially-affects-discrete-subpopulations-of-splenic-macrophages
#4
Laura McCulloch, Alessio Alfieri, Barry W McColl
Changes to the immune system after stroke are complex and can result in both pro-inflammatory and immunosuppressive consequences. Following ischemic stroke, brain resident microglia are activated and circulating monocytes are recruited to the injury site. In contrast, there is a systemic deactivation of monocytes/macrophages that may contribute to immunosuppression and the high incidence of bacterial infection experienced by stroke patients. The manipulation of macrophage subsets may be a useful therapeutic strategy to reduce infection and improve outcome in patients after stroke...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29790105/physostigmine-restores-impaired-autophagy-in-the-rat-hippocampus-after-surgery-stress-and-lps-treatment
#5
Clarissa von Haefen, Marco Sifringer, Stefanie Endesfelder, Alexander Kalb, Adrián González-López, Annalena Tegethoff, Nadine Paeschke, Claudia D Spies
Tissue damage and pathogen invasion during surgical trauma have been identified as contributing factors leading to neuroinflammation in the hippocampus, which can be protected by stimulation of the cholinergic anti-inflammatory pathway using the acetylcholinesterase inhibitor physostigmine. Macroautophagy, an intracellular degradation pathway used to recycle and eliminate damaged proteins and organelles by lysosomal digestion, seems to be important for cell survival under stress conditions. This study aimed to examine the role of autophagy in physostigmine-mediated hippocampal cell protection in a rat model of surgery stress...
May 22, 2018: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/29777152/temporary-microglia-depletion-after-cosmic-radiation-modifies-phagocytic-activity-and-prevents-cognitive-deficits
#6
Karen Krukowski, Xi Feng, Maria Serena Paladini, Austin Chou, Kristen Sacramento, Katherine Grue, Lara-Kirstie Riparip, Tamako Jones, Mary Campbell-Beachler, Gregory Nelson, Susanna Rosi
Microglia are the main immune component in the brain that can regulate neuronal health and synapse function. Exposure to cosmic radiation can cause long-term cognitive impairments in rodent models thereby presenting potential obstacles for astronauts engaged in deep space travel. The mechanism/s for how cosmic radiation induces cognitive deficits are currently unknown. We find that temporary microglia depletion, one week after cosmic radiation, prevents the development of long-term memory deficits. Gene array profiling reveals that acute microglia depletion alters the late neuroinflammatory response to cosmic radiation...
May 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29771310/fingolimod-phosphate-inhibits-astrocyte-inflammatory-activity-in-mucolipidosis-iv
#7
Laura Weinstock, Amanda M Furness, Shawn Herron, Sierra S Smith, Sitara Sankar, Samantha G DeRosa, Dadi Gao, Molly E Mepyans, Anna Scotto Rosato, Diego L Medina, Ayelet Vardi, Natalia S Ferreira, Soo Min Cho, Anthony H Futerman, Susan A Slaugenhaupt, Levi B Wood, Yulia Grishchuk
Mucolipidosis IV (MLIV) is an orphan neurodevelopmental disease that causes severe neurologic dysfunction and loss of vision. Currently there is no therapy for MLIV. It is caused by loss of function of the lysosomal channel mucolipin-1, also known as TRPML1. Knockout of the Mcoln1 gene in a mouse model mirrors clinical and neuropathological signs in humans. Using this model, we previously observed robust activation of microglia and astrocytes in early symptomatic stages of disease. Here we investigate the consequence of mucolipin-1 loss on astrocyte inflammatory activation in vivo and in vitro and apply a pharmacological approach to restore Mcoln1-/- astrocyte homeostasis using a clinically approved immunomodulator, fingolimod...
May 16, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29755317/microglial-phagocytosis-and-its-regulation-a-therapeutic-target-in-parkinson-s-disease
#8
REVIEW
Elzbieta Janda, Laura Boi, Anna R Carta
The role of phagocytosis in the neuroprotective function of microglia has been appreciated for a long time, but only more recently a dysregulation of this process has been recognized in Parkinson's disease (PD). Indeed, microglia play several critical roles in central nervous system (CNS), such as clearance of dying neurons and pathogens as well as immunomodulation, and to fulfill these complex tasks they engage distinct phenotypes. Regulation of phenotypic plasticity and phagocytosis in microglia can be impaired by defects in molecular machinery regulating critical homeostatic mechanisms, including autophagy...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29740932/antagonizing-peroxisome-proliferator-activated-receptor-%C3%AE-facilitates-m1-to-m2-shift-of-microglia-by-enhancing-autophagy-via-the-lkb1-ampk-signaling-pathway
#9
Juan Ji, Teng-Fei Xue, Xu-Dong Guo, Jin Yang, Ruo-Bing Guo, Juan Wang, Ji-Ye Huang, Xiao-Jie Zhao, Xiu-Lan Sun
Microglia-mediated neuroinflammation plays a dual role in various brain diseases due to distinct microglial phenotypes, including deleterious M1 and neuroprotective M2. There is growing evidence that the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone prevents lipopolysaccharide (LPS)-induced microglial activation. Here, we observed that antagonizing PPARγ promoted LPS-stimulated changes in polarization from the M1 to the M2 phenotype in primary microglia. PPARγ antagonist T0070907 increased the expression of M2 markers, including CD206, IL-4, IGF-1, TGF-β1, TGF-β2, TGF-β3, G-CSF, and GM-CSF, and reduced the expression of M1 markers, such as CD86, Cox-2, iNOS, IL-1β, IL-6, TNF-α, IFN-γ, and CCL2, thereby inhibiting NFκB-IKKβ activation...
May 8, 2018: Aging Cell
https://www.readbyqxmd.com/read/29729668/urmc-099-facilitates-amyloid-%C3%AE-clearance-in-a-murine-model-of-alzheimer-s-disease
#10
Tomomi Kiyota, Jatin Machhi, Yaman Lu, Bhagyalaxmi Dyavarshetty, Maryam Nemati, Gang Zhang, R Lee Mosley, Harris A Gelbard, Howard E Gendelman
BACKGROUND: The mixed lineage kinase type 3 inhibitor URMC-099 facilitates amyloid-beta (Aβ) clearance and degradation in cultured murine microglia. One putative mechanism is an effect of URMC-099 on Aβ uptake and degradation. As URMC-099 promotes endolysosomal protein trafficking and reduces Aβ microglial pro-inflammatory activities, we assessed whether these responses affect Aβ pathobiogenesis. To this end, URMC-099's therapeutic potential, in Aβ precursor protein/presenilin-1 (APP/PS1) double-transgenic mice, was investigated in this model of Alzheimer's disease (AD)...
May 5, 2018: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29719536/phosphatidyl-inositol-3-kinase-inhibitors-regulate-peptidoglycan-induced-myeloid-leukocyte-recruitment-inflammation-and-neurotoxicity-in-mouse-brain
#11
Daniela S Arroyo, Emilia A Gaviglio, Javier M Peralta Ramos, Claudio Bussi, Maria P Avalos, Liliana M Cancela, Pablo Iribarren
Acute brain injury leads to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral myeloid cells (MC), which contribute to the inflammatory response involved in neuronal damage. We previously reported that TLR2 stimulation by peptidoglycan (PGN) from Staphylococcus aureus, in vitro and in vivo , induced microglial cell activation followed by autophagy induction. In this report, we evaluated if phosphatidyl-inositol-3 kinase (PI3K) pharmacological inhibitors LY294200 and 3-methyladenine (3-MA) can modulate the innate immune response to PGN in the central nervous system...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29718288/the-pathogenesis-of-lysosomal-storage-disorders-beyond-the-engorgement-of-lysosomes-to-abnormal-development-and-neuroinflammation
#12
Maria Teresa Fiorenza, Enrico Moro, Robert P Erickson
There is growing evidence that the complex clinical manifestations of lysosomal storage diseases (LSDs) are not fully explained by the engorgement of the endosomal-autophagic-lysosomal system. In this review, we explore current knowledge of common pathogenetic mechanisms responsible for the early onset of tissue abnormalities of two LSDs, Mucopolysaccharidosis type II (MPSII) and Niemann-Pick type C (NPC) diseases. In particular, perturbations of the homeostasis of glycosaminoglycans (GAGs) and cholesterol (Chol) in MPSII and NPC diseases, respectively, affect key biological processes, including morphogen signaling...
April 28, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29679260/slow-release-of-hiv-1-protein-nef-from-vesicle-like-structures-is-inhibited-by-cytosolic-calcium-elevation-in-single-human-microglia
#13
Matjaž Stenovec, Eva Lasič, Pia Pužar Dominkuš, Saša Trkov Bobnar, Robert Zorec, Metka Lenassi, Marko Kreft
Once infected by HIV-1, microglia abundantly produce accessory protein Nef that enhances virus production and infectivity, but little is known about its intracellular compartmentalization, trafficking mode(s), and release from microglia. Here, we transfected immortalized human microglia with a plasmid encoding Nef tagged with green fluorescent protein (Nef.GFP) to biochemically and microscopically identify Nef.GFP-associated cellular compartments and examine their mobility and Nef release from cultured cells...
April 21, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29662435/ac2-26-induces-ikk%C3%AE-degradation-through-chaperone-mediated-autophagy-via-hspb1-in-ncm-treated-microglia
#14
Lu Liu, Dandan An, Junying Xu, Bin Shao, Xing Li, Jing Shi
Annexin A1 (ANXA1) is an endogenous protein with potent anti-inflammatory properties in the brain. Although ANXA1 has been predominantly studied for its binding to formyl peptide receptors (FPRs) on plasma membranes, little is known regarding whether this protein has an anti-inflammatory effect in the cytosol. Here, we investigated the mechanism by which the ANXA1 peptide Ac2-26 decreases high TNF-α production and IKKβ activity, which was caused by oxygen glucose deprivation/reperfusion (OGD/R)-induced neuronal conditioned medium (NCM) in microglia...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29492824/inflammasome-activation-by-methamphetamine-potentiates-lipopolysaccharide-stimulation-of-il-1%C3%AE-production-in-microglia
#15
Enquan Xu, Jianuo Liu, Han Liu, Xiaobei Wang, Huangui Xiong
Methamphetamine (Meth) is an addictive psychostimulant abused worldwide. Ample evidence indicate that chronic abuse of Meth induces neurotoxicity via microglia-associated neuroinflammation and the activated microglia present in both Meth-administered animals and human abusers. The development of anti-neuroinflammation as a therapeutic strategy against Meth dependence promotes research to identify inflammatory pathways that are specifically tied to Meth-induced neurotoxicity. Currently, the exact mechanisms for Meth-induced microglia activation are largely unknown...
June 2018: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/29443098/a-novel-in-vitro-live-imaging-assay-of-astrocyte-mediated-phagocytosis-using-ph-indicator-conjugated-synaptosomes
#16
Youkyeong Gloria Byun, Won-Suk Chung
Astrocytes are the major cell type in the brain and directly contact synapses and blood vessels. Although microglial cells have been considered the major immune cells and only phagocytes in the brain, recent studies have shown that astrocytes also participate in various phagocytic processes, such as developmental synapse elimination and clearance of amyloid beta plaques in Alzheimer's disease (AD). Despite these findings, the efficiency of astrocyte engulfment and degradation of their targets is unclear compared with that of microglia...
February 5, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29378960/lysosomal-enzyme-tripeptidyl-peptidase-1-destabilizes-fibrillar-a%C3%AE-by-multiple-endoproteolytic-cleavages-within-the-%C3%AE-sheet-domain
#17
Santiago Solé-Domènech, Ana V Rojas, Gia G Maisuradze, Harold A Scheraga, Peter Lobel, Frederick R Maxfield
Accumulation of amyloid-beta (Aβ), which is associated with Alzheimer's disease, can be caused by excess production or insufficient clearance. Because of its β-sheet structure, fibrillar Aβ is resistant to proteolysis, which would contribute to slow degradation of Aβ plaques in vivo. Fibrillar Aβ can be internalized by microglia, which are the scavenger cells of the brain, but the fibrils are degraded only slowly in microglial lysosomes. Cathepsin B is a lysosomal protease that has been shown to proteolyze fibrillar Aβ...
February 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29378861/progranulin-gene-therapy-improves-lysosomal-dysfunction-and-microglial-pathology-associated-with-frontotemporal-dementia-and-neuronal-ceroid-lipofuscinosis
#18
Andrew E Arrant, Vincent C Onyilo, Daniel E Unger, Erik D Roberson
Loss-of-function mutations in progranulin, a lysosomal glycoprotein, cause neurodegenerative disease. Progranulin haploinsufficiency causes frontotemporal dementia (FTD) and complete progranulin deficiency causes CLN11 neuronal ceroid lipofuscinosis (NCL). Progranulin replacement is a rational therapeutic strategy for these disorders, but there are critical unresolved mechanistic questions about a progranulin gene therapy approach, including its potential to reverse existing pathology. Here, we address these issues using an AAV vector (AAV- Grn ) to deliver progranulin in Grn -/- mice (both male and female), which model aspects of NCL and FTD pathology, developing lysosomal dysfunction, lipofuscinosis, and microgliosis...
February 28, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29369397/metallothioneins-are-neuroprotective-agents-in-lysosomal-storage-disorders
#19
Eleonora Cavalca, Martina Cesani, Jennifer Gifford, Miguel Sena Esteves, Maria Rosa Terreni, Giuseppe Leoncini, Marco Peviani, Alessandra Biffi
OBJECTIVE: Lysosomal Storage Disorders (LSDs) are a broad class of inherited metabolic diseases caused by the defective activity of lysosomal enzymes. Central nervous system (CNS) manifestations are present in roughly 50% of LSD patients and represent an unmet medical need for them. We explored the therapeutic potential of Metallothioneins (MTs), a newly identified family of proteins with reported neuroprotective roles, in the murine models of two LSDs with CNS involvement. METHODS: MT-1 over-expressing transgenic mice (MTtg) were crossed with the murine models of Batten and Krabbe diseases...
January 25, 2018: Annals of Neurology
https://www.readbyqxmd.com/read/29340649/optic-nerve-regeneration-after-crush-remodels-the-injury-site-molecular-insights-from-imaging-mass-spectrometry
#20
David T Stark, David M G Anderson, Jacky M K Kwong, Nathan Heath Patterson, Kevin L Schey, Richard M Caprioli, Joseph Caprioli
Purpose: Mammalian central nervous system axons fail to regenerate after injury. Contributing factors include limited intrinsic growth capacity and an inhibitory glial environment. Inflammation-induced optic nerve regeneration (IIR) is thought to boost retinal ganglion cell (RGC) intrinsic growth capacity through progrowth gene expression, but effects on the inhibitory glial environment of the optic nerve are unexplored. To investigate progrowth molecular changes associated with reactive gliosis during IIR, we developed an imaging mass spectrometry (IMS)-based approach that identifies discriminant molecular signals in and around optic nerve crush (ONC) sites...
January 1, 2018: Investigative Ophthalmology & Visual Science
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