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https://www.readbyqxmd.com/read/27889490/inhibition-of-cathepsin-x-reduces-the-strength-of-microglial-mediated-neuroinflammation
#1
Anja Pišlar, Biljana Božić, Nace Zidar, Janko Kos
Inflammation plays a central role in the processes associated with neurodegeneration. The inflammatory response is mediated by activated microglia that release inflammatory mediators to the neuronal environment. Microglia-derived lysosomal cathepsins, including cathepsin X, are increasingly recognized as important mediators of the inflammation involved in lipopolysaccharide (LPS)-induced neuroinflammation. The current study was undertaken to investigate the role of cathepsin X and its molecular target, γ-enolase, in neuroinflammation and to elucidate the underlying mechanism...
November 23, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27888296/toll-like-receptor-2-is-increased-in-neurons-in-parkinson-s-disease-brain-and-may-contribute-to-alpha-synuclein-pathology
#2
Nicolas Dzamko, Amanda Gysbers, Gayathri Perera, Anita Bahar, Amrita Shankar, Jianqun Gao, YuHong Fu, Glenda M Halliday
Inflammation is likely a key contributor to the pathogenesis of Parkinson's disease (PD), a progressively debilitating neurodegenerative disease that is accompanied by a pathological accumulation of the α-synuclein protein in a staged manner through the brain. What leads to the accumulation of α-synuclein in PD and how this relates to inflammatory pathways, however, is not entirely clear. Toll-like receptor (TLR) signaling is a major pathway mediating inflammation and, in particular, TLR2 is increasingly being implicated in PD...
November 25, 2016: Acta Neuropathologica
https://www.readbyqxmd.com/read/27830533/analysis-of-the-impact-of-cd200-on-phagocytosis
#3
Anthony Lyons, Aedín M Minogue, Raasay S Jones, Orla Fitzpatrick, Janis Noonan, Veronica A Campbell, Marina A Lynch
One factor that impacts on microglial activation is the interaction between the ubiquitously expressed CD200 and CD200R, which is expressed only on microglia in the brain. Decreased signalling through CD200R, when CD200 expression is reduced, results in microglial activation and may, at least in part, explain the increased cell activity that is observed with age, in models of Alzheimer's and Parkinson's disease as well as in the human diseases. There is evidence of increased microglial activation in CD200-deficient mice, and isolated microglia prepared from these mice are more reactive to inflammatory stimuli like Toll-like receptor 2 and 4 agonists, and interferon-γ...
November 9, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27793778/aav-mediated-gene-delivery-attenuates-neuroinflammation-in-feline-sandhoff-disease
#4
Allison M Bradbury, Tiffany A Peterson, Amanda L Gross, Stephen Z Wells, Victoria J McCurdy, Karen G Wolfe, John C Dennis, Brandon L Brunson, Heather Gray-Edwards, Ashley N Randle, Aime K Johnson, Edward E Morrison, Nancy R Cox, Henry J Baker, Miguel Sena-Esteves, Douglas R Martin
Sandhoff disease (SD) is a lysosomal storage disorder characterized by the absence of hydrolytic enzyme β-N-acetylhexosaminidase (Hex), which results in storage of GM2 ganglioside in neurons and unremitting neurodegeneration. Neuron loss initially affects fine motor skills, but rapidly progresses to loss of all body faculties, a vegetative state, and death by five years of age in humans. A well-established feline model of SD allows characterization of the disease in a large animal model and provides a means to test the safety and efficacy of therapeutic interventions before initiating clinical trials...
October 26, 2016: Neuroscience
https://www.readbyqxmd.com/read/27742410/baicalein-attenuates-%C3%AE-synuclein-aggregation-inflammasome-activation-and-autophagy-in-the-mpp-treated-nigrostriatal-dopaminergic-system-in-vivo
#5
Kai-Chih Hung, Hui-Ju Huang, Yi-Ting Wang, Anya Maan-Yuh Lin
ETHNOPHARMACOLOGICAL RELEVANCE: Neuroinflammation, oxidative stress, and protein aggregation form a vicious cycle in the pathophysiology of Parkinson's disease (PD); activated microglia is the main location of neuroinflammation. A Chinese medicine book, "Shanghan Lun", known as the "Treatises on Cold damage Diseases" has suggested that Scutellaria baicalensis Georgi is effective in treating CNS diseases. The anti-inflammatory mechanisms of baicalein, a phenolic flavonoid in the dried root of Scutellaria baicalensis Georgi, remain to be explored...
October 11, 2016: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/27717139/vps35-dependent-recycling-of-trem2-regulates-microglial-function
#6
Jie Yin, Xiaocui Liu, Qing He, Lujun Zhou, Zengqiang Yuan, Siqi Zhao
Triggering receptor expressed on myeloid cells 2 (Trem2), an immune-modulatory receptor, is preferentially expressed in microglia of central nervous system. Trem2 might be involved in the development of Alzheimer's disease (AD) through regulating the inflammatory responses and phagocytosis of microglia. However, the intracellular trafficking of Trem2 remains unclear. In this study, we showed that Trem2 in the plasma membrane underwent endocytosis and recycling. Trem2 is internalized in a clathrin-dependent manner and then recycled back to the plasma membrane through vacuolar protein sorting 35 (Vps35), the key component of cargo recognition core of retromer complex, but not Rab11...
September 26, 2016: Traffic
https://www.readbyqxmd.com/read/27554659/microglia-senescence-impairs-clearance-of-myelin-debris
#7
Peter Thériault, Serge Rivest
Growing evidence highlights the crucial physiological functions of microglia that rely on their phagocytic activities, which can be compromised with age. A new study reports the impaired clearance of myelin debris by microglia in the brain, leading to insoluble lysosomal inclusions and contributing to the immune dysfunction and senescence of these cells.
August 22, 2016: Current Biology: CB
https://www.readbyqxmd.com/read/27531183/amyloid-%C3%AE-42-protofibrils-are-internalized-by-microglia-more-extensively-than-monomers
#8
Lisa K Gouwens, Nyasha J Makoni, Victoria A Rogers, Michael R Nichols
One pathological hallmark of Alzheimer's disease (AD) is the accumulation of amyloid-β peptide (Aβ) in the affected brain. While there are numerous deleterious effects of Aβ accumulation, there is general agreement that a sustained inflammatory response to aggregated Aβ contributes to progressive neurodegeneration in AD and microglial cells play a significant role in this process. Our laboratory and others have shown that small soluble aggregates of Aβ activate a microglia-mediated inflammatory response...
October 1, 2016: Brain Research
https://www.readbyqxmd.com/read/27497943/mesenchymal-stem-cells-enhance-%C3%AE-synuclein-clearance-via-m2-microglia-polarization-in-experimental-and-human-parkinsonian-disorder
#9
Hyun Jung Park, Se Hee Oh, Ha Na Kim, Yu Ju Jung, Phil Hyu Lee
Microglia in the brain show distinctive phenotypes that serve different functions. In particular, M2-polarized microglia are anti-inflammatory and phagocytic cells that serve a restorative function. In this study, we investigated whether mesenchymal stem cells (MSCs) enhance the phagocytic clearance of α-synuclein via M2 microglia polarization, and thereby exert neuroprotective effects in α-synuclein-enriched experimental models and patients with multiple system atrophy (MSA). Treatment of BV2 cells with α-synuclein induced an inflammatory phenotype, whereas co-culture of α-synuclein-treated BV2 cells with MSCs induced an anti-inflammatory M2 phenotype, with decreased α-synuclein levels and increased lysosomal activity, leading to greater viability of neuronal cells co-cultured with BV2 cells...
November 2016: Acta Neuropathologica
https://www.readbyqxmd.com/read/27453479/accumulated-%C3%AE-synuclein-affects-the-progression-of-gm2-gangliosidoses
#10
Kyoko Suzuki, Akira Yamaguchi, Shoji Yamanaka, Seiichi Kanzaki, Masato Kawashima, Takashi Togo, Omi Katsuse, Noriko Koumitsu, Naoya Aoki, Eizo Iseki, Kenji Kosaka, Kayoko Yamaguchi, Makoto Hashimoto, Ichiro Aoki, Yoshio Hirayasu
The accumulation of α-synuclein (ASyn) has been observed in several lysosomal storage diseases (LSDs) but it remains unclear if ASyn accumulation contributes to LSD pathology. ASyn also accumulates in the neurons of Sandhoff disease (SD) patients and SD model mice (Hexb-/- ASyn+/+ mice). SD is a lysosomal storage disorder caused by the absence of a functional β-subunit on the β-hexosaminidase A and B enzymes, which leads to the accumulation of ganglioside in the central nervous system. Here, we explored the role of accumulated ASyn in the progression of Hexb-/- mice by creating a Hexb-/- ASyn-/- double-knockout mice...
July 21, 2016: Experimental Neurology
https://www.readbyqxmd.com/read/27425031/transcriptional-profiling-of-cd11c-positive-microglia-accumulating-around-amyloid-plaques-in-a-mouse-model-for-alzheimer-s-disease
#11
Willem Kamphuis, Lieneke Kooijman, Sjoerd Schetters, Marie Orre, Elly M Hol
Amyloid plaques in Alzheimer's disease (AD) mice are surrounded by activated microglia. The functional role of microglia activation in AD is not well understood; both detrimental and beneficial effects on AD progression have been reported. Here we show that the population of activated microglia in the cortex of the APPswe/PS1dE9 mouse AD model is divided into a CD11c-positive and a CD11c-negative subpopulation. Cd11c transcript levels and number of CD11c-positive microglia increase sharply when plaques start to occur and both parameters continue to rise in parallel with the age-related increasing plaque load...
October 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27421577/the-endocytic-pathway-in-microglia-during-health-aging-and-alzheimer-s-disease
#12
REVIEW
Santiago Solé-Domènech, Dana L Cruz, Estibaliz Capetillo-Zarate, Frederick R Maxfield
Microglia, the main phagocytes of the central nervous system (CNS), are involved in the surveillance and maintenance of nervous tissue. During normal tissue homeostasis, microglia migrates within the CNS, phagocytose dead cells and tissue debris, and modulate synapse pruning and spine formation via controlled phagocytosis. In the event of an invasion by a foreign body, microglia are able to phagocytose the invading pathogen and process it proteolytically for antigen presentation. Internalized substrates are incorporated and sorted within the endocytic pathway and thereafter transported via complex vesicular routes...
December 2016: Ageing Research Reviews
https://www.readbyqxmd.com/read/27364756/interleukin-1%C3%AE-has-trophic-effects-in-microglia-and-its-release-is-mediated-by-p2x7r-pore
#13
Mastura Monif, Christopher A Reid, Kim L Powell, Katherine J Drummond, Terrence J O'Brien, David A Williams
BACKGROUND: Enhanced expression of the purinergic P2X7 receptor (P2X7R) occurs in several neuroinflammatory conditions where increased microglial activation is a co-existing feature. P2X7 receptors can function either as a cation channel or, upon continued stimulation, a large pore. P2X7R-over-expression alone is sufficient to drive microglial activation and proliferation in a process that is P2X7R pore dependent, although the biological signaling pathway through which this occurs remains unclear...
2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27294511/age-related-myelin-degradation-burdens-the-clearance-function-of-microglia-during-aging
#14
Shima Safaiyan, Nirmal Kannaiyan, Nicolas Snaidero, Simone Brioschi, Knut Biber, Simon Yona, Aimee L Edinger, Steffen Jung, Moritz J Rossner, Mikael Simons
Myelin is synthesized as a multilamellar membrane, but the mechanisms of membrane turnover are unknown. We found that myelin pieces were gradually released from aging myelin sheaths and were subsequently cleared by microglia. Myelin fragmentation increased with age and led to the formation of insoluble, lipofuscin-like lysosomal inclusions in microglia. Thus, age-related myelin fragmentation is substantial, leading to lysosomal storage and contributing to microglial senescence and immune dysfunction in aging...
August 2016: Nature Neuroscience
https://www.readbyqxmd.com/read/27270598/suppression-of-the-motor-deficit-in-a-mucolipidosis-type-iv-mouse-model-by-bone-marrow-transplantation
#15
Marquis T Walker, Craig Montell
Mucolipidosis IV (MLIV) is a severe lysosomal storage disorder, which results from loss of the TRPML1 channel. MLIV causes multiple impairments in young children, including severe motor deficits. Currently, there is no effective treatment. Using a Drosophila MLIV model, we showed previously that introduction of trpml(+ )in phagocytic glia rescued the locomotor deficit by removing early dying neurons, thereby preventing amplification of neuronal death from cytotoxicity. Because microglia, which are phagocytic cells in the mammalian brain, are bone marrow derived, and cross the blood-brain barrier, we used a mouse MLIV model to test the efficacy of bone marrow transplantation (BMT)...
June 7, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27216632/indirect-effects-of-tio2-nanoparticle-on-neuron-glial-cell-interactions
#16
I-Lun Hsiao, Chia-Cheng Chang, Chung-Yi Wu, Yi-Kong Hsieh, Chun-Yu Chuang, Chu-Fang Wang, Yuh-Jeen Huang
Although, titanium dioxide nanoparticles (TiO2NPs) are nanomaterials commonly used in consumer products, little is known about their hazardous effects, especially on central nervous systems. To examine this issue, ALT astrocyte-like, BV-2 microglia and differentiated N2a neuroblastoma cells were exposed to 6 nm of 100% anatase TiO2NPs. A lipopolysaccharide (LPS) was pre-treated to activate glial cells before NP treatment for mimicking NP exposure under brain injury. We found that ALT and BV-2 cells took up more NPs than N2a cells and caused lower cell viability...
July 25, 2016: Chemico-biological Interactions
https://www.readbyqxmd.com/read/27215202/progranulin-protects-hippocampal-neurogenesis-via-suppression-of-neuroinflammatory-responses-under-acute-immune-stress
#17
Yanbo Ma, Takashi Matsuwaki, Keitaro Yamanouchi, Masugi Nishihara
Immune stress is well known to suppress adult neurogenesis in the hippocampus. We have demonstrated that progranulin (PGRN) has a mitogenic effect on neurogenesis under several experimental conditions. We have also shown that PGRN suppresses excessive neuroinflammatory responses after traumatic brain injury. However, the role of PGRN in modulating neurogenesis under acute immune stress is yet to be elucidated. In the present study, we evaluated the involvement of PGRN in neurogenesis and inflammatory responses in the hippocampus using a lipopolysaccharide (LPS)-induced immune stress model...
May 23, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27209302/deacetylation-of-tfeb-promotes-fibrillar-a%C3%AE-degradation-by-upregulating-lysosomal-biogenesis-in-microglia
#18
Jintao Bao, Liangjun Zheng, Qi Zhang, Xinya Li, Xuefei Zhang, Zeyang Li, Xue Bai, Zhong Zhang, Wei Huo, Xuyang Zhao, Shujiang Shang, Qingsong Wang, Chen Zhang, Jianguo Ji
Microglia play a pivotal role in clearance of Aβ by degrading them in lysosomes, countering amyloid plaque pathogenesis in Alzheimer's disease (AD). Recent evidence suggests that lysosomal dysfunction leads to insufficient elimination of toxic protein aggregates. We tested whether enhancing lysosomal function with transcription factor EB (TFEB), an essential regulator modulating lysosomal pathways, would promote Aβ clearance in microglia. Here we show that microglial expression of TFEB facilitates fibrillar Aβ (fAβ) degradation and reduces deposited amyloid plaques, which are further enhanced by deacetylation of TFEB...
June 2016: Protein & Cell
https://www.readbyqxmd.com/read/27175482/induction-of-the-type-i-interferon-response-in-neurological-forms-of-gaucher-disease
#19
Einat B Vitner, Tamar Farfel-Becker, Natalia Santos Ferreira, Dena Leshkowitz, Piyush Sharma, Karl S Lang, Anthony H Futerman
BACKGROUND: Neuroinflammation is a key phenomenon in the pathogenesis of many neurodegenerative diseases. Understanding the mechanisms by which brain inflammation is engaged and delineating the key players in the immune response and their contribution to brain pathology is of great importance for the identification of novel therapeutic targets for these devastating diseases. Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the GBA1 gene and is a significant risk factor for Parkinson's disease; in some forms of Gaucher disease, neuroinflammation is observed...
2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27171064/tfeb-and-tfe3-cooperate-in-the-regulation-of-the-innate-immune-response-in-activated-macrophages
#20
Nunzia Pastore, Owen A Brady, Heba I Diab, José A Martina, Lu Sun, Tuong Huynh, Jeong-A Lim, Hossein Zare, Nina Raben, Andrea Ballabio, Rosa Puertollano
The activation of transcription factors is critical to ensure an effective defense against pathogens. In this study we identify a critical and complementary role of the transcription factors TFEB and TFE3 in innate immune response. By using a combination of chromatin immunoprecipitation, CRISPR-Cas9-mediated genome-editing technology, and in vivo models, we determined that TFEB and TFE3 collaborate with each other in activated macrophages and microglia to promote efficient autophagy induction, increased lysosomal biogenesis, and transcriptional upregulation of numerous proinflammatory cytokines...
August 2, 2016: Autophagy
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