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Microglia and lysosome

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https://www.readbyqxmd.com/read/29443098/a-novel-in-vitro-live-imaging-assay-of-astrocyte-mediated-phagocytosis-using-ph-indicator-conjugated-synaptosomes
#1
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
#2
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...
January 29, 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
#3
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...
January 29, 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
#4
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
#5
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
https://www.readbyqxmd.com/read/29226242/intracerebroventricular-delivery-of-hematopoietic-progenitors-results-in-rapid-and-robust-engraftment-of-microglia-like-cells
#6
Alessia Capotondo, Rita Milazzo, Jose M Garcia-Manteiga, Eleonora Cavalca, Annita Montepeloso, Brian S Garrison, Marco Peviani, Derrick J Rossi, Alessandra Biffi
Recent evidence indicates that hematopoietic stem and progenitor cells (HSPCs) can serve as vehicles for therapeutic molecular delivery to the brain by contributing to the turnover of resident myeloid cell populations. However, such engraftment needs to be fast and efficient to exert its therapeutic potential for diseases affecting the central nervous system. Moreover, the nature of the cells reconstituted after transplantation and whether they could comprise bona fide microglia remain to be assessed. We demonstrate that transplantation of HSPCs in the cerebral lateral ventricles provides rapid engraftment of morphologically, antigenically, and transcriptionally dependable microglia-like cells...
December 2017: Science Advances
https://www.readbyqxmd.com/read/29179879/p2x4-a-fast-and-sensitive-purinergic-receptor
#7
REVIEW
Jaanus Suurväli, Pierre Boudinot, Jean Kanellopoulos, Sirje Rüütel Boudinot
Extracellular nucleotides have been recognized as important mediators of activation, triggering multiple responses via plasma membrane receptors known as P2 receptors. P2 receptors comprise P2X ionotropic receptors and G protein-coupled P2Y receptors. P2X receptors are expressed in many tissues, where they are involved in a number of functions including synaptic transmission, muscle contraction, platelet aggregation, inflammation, macrophage activation, differentiation and proliferation, neuropathic and inflammatory pain...
October 2017: Biomedical Journal
https://www.readbyqxmd.com/read/29167375/loss-of-apobec1-rna-editing-function-in-microglia-exacerbates-age-related-cns-pathophysiology
#8
Daniel C Cole, Youngcheul Chung, Khatuna Gagnidze, Kaitlyn H Hajdarovic, Violeta Rayon-Estrada, Dewi Harjanto, Benedetta Bigio, Judit Gal-Toth, Teresa A Milner, Bruce S McEwen, F Nina Papavasiliou, Karen Bulloch
Microglia (MG), a heterogeneous population of phagocytic cells, play important roles in central nervous system (CNS) homeostasis and neural plasticity. Under steady-state conditions, MG maintain homeostasis by producing antiinflammatory cytokines and neurotrophic factors, support myelin production, and remove synapses and cellular debris, as well as participating in "cross-correction," a process that supplies neurons with key factors for executing autophagy-lysosomal function. As sentinels for the immune system, MG also detect "danger" signals (pathogenic or traumatic insult), become activated, produce proinflammatory cytokines, and recruit monocytes and dendritic cells to the site of damage through a breached blood-brain barrier or via brain lymphatics...
December 12, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29132391/nadph-oxidases-in-parkinson-s-disease-a-systematic-review
#9
REVIEW
Karim Belarbi, Elodie Cuvelier, Alain Destée, Bernard Gressier, Marie-Christine Chartier-Harlin
Parkinson's disease (PD) is a progressive movement neurodegenerative disease associated with a loss of dopaminergic neurons in the substantia nigra of the brain. Oxidative stress, a condition that occurs due to imbalance in oxidant and antioxidant status, is thought to play an important role in dopaminergic neurotoxicity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are multi-subunit enzymatic complexes that generate reactive oxygen species as their primary function. Increased immunoreactivities for the NADPH oxidases catalytic subunits Nox1, Nox2 and Nox4 have been reported in the brain of PD patients...
November 13, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29061383/release-of-soluble-and-vesicular-purine-nucleoside-phosphorylase-from-rat-astrocytes-and-microglia-induced-by-pro-inflammatory-stimulation-with-extracellular-atp-via-p2x7-receptors
#10
Luis Emiliano Peña-Altamira, Elisabetta Polazzi, Patricia Giuliani, Alina Beraudi, Francesca Massenzio, Ilaria Mengoni, Alessandro Poli, Mariachiara Zuccarini, Renata Ciccarelli, Patrizia Di Iorio, Marco Virgili, Barbara Monti, Francesco Caciagli
Purine nucleoside phosphorylase (PNP), a crucial enzyme in purine metabolism which converts ribonucleosides into purine bases, has mainly been found inside glial cells. Since we recently demonstrated that PNP is released from rat C6 glioma cells, we then wondered whether this occurs in normal brain cells. Using rat primary cultures of microglia, astrocytes and cerebellar granule neurons, we found that in basal condition all these cells constitutively released a metabolically active PNP with Km values very similar to those measured in C6 glioma cells...
October 20, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/29057315/mitochondrial-impairment-in-microglia-amplifies-nlrp3-inflammasome-proinflammatory-signaling-in-cell-culture-and-animal-models-of-parkinson-s-disease
#11
Souvarish Sarkar, Emir Malovic, Dilshan S Harishchandra, Shivani Ghaisas, Nikhil Panicker, Adhithiya Charli, Bharathi N Palanisamy, Dharmin Rokad, Huajun Jin, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G Kanthasamy
The NLRP3 inflammasome signaling pathway is a major contributor to the neuroinflammatory process in the central nervous system. Oxidative stress and mitochondrial dysfunction are key pathophysiological processes of many chronic neurodegenerative diseases, including Parkinson's disease (PD). However, the inter-relationship between mitochondrial defects and neuroinflammation is not well understood. In the present study, we show that impaired mitochondrial function can augment the NLRP3 inflammasome-driven proinflammatory cascade in microglia...
2017: NPJ Parkinson's Disease
https://www.readbyqxmd.com/read/29025968/activation-of-ampk-mtorc1-mediated-autophagy-by-metformin-reverses-clk1-deficiency-sensitized-dopaminergic-neuronal-death
#12
Qiuting Yan, Chaojun Han, Guanghui Wang, John L Waddington, Longtai Zheng, Xuechu Zhen
The autophagy-lysosome pathway (ALP) plays a critical role in the pathology of Parkinson's disease (PD). Clk1 (coq7) is a mitochondrial hydroxylase that is essential for coenzyme Q (ubiquinone) biosynthesis. We have reported previously that Clk1 regulates microglia activation via modulating microglia metabolic reprogramming, which contributes to dopaminergic neuronal survival. This study explores the direct effect of Clk1 on dopaminergic neuronal survival. We demonstrate that Clk1 deficiency inhibited dopaminergic neuronal autophagy in cultured MN9D dopaminergic neurons and in the substantia nigra pars compacta of Clk+/- mutant mice and consequently sensitized dopaminergic neuron damage and behavioral defects...
December 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28986232/rifampicin-inhibits-rotenone-induced-microglial-inflammation-via-enhancement-of-autophagy
#13
Yanran Liang, Tianen Zhou, Ying Chen, Danyu Lin, Xiuna Jing, Sudan Peng, Dezhi Zheng, Zhifen Zeng, Ming Lei, Xia Wu, Kaixun Huang, Lianhong Yang, Songhua Xiao, Jun Liu, Enxiang Tao
Mitochondrial and autophagic dysfunction, as well as neuroinflammation, are associated with the pathophysiology of Parkinson's disease (PD). Rotenone, an inhibitor of mitochondrial complex I, has been associated as an environmental neurotoxin related to PD. Our previous studies reported that rifampicin inhibited microglia activation and production of proinflammatory mediators induced by rotenone, but the precise mechanism has not been completely elucidated. BV2 cells were pretreated for 2h with rifampicin followed by 0...
October 3, 2017: Neurotoxicology
https://www.readbyqxmd.com/read/28969867/anti-inflammatory-m2-macrophage-media-reduce-transmission-of-oligomeric-amyloid-beta-in-differentiated-sh-sy5y-cells
#14
Valerie Sackmann, Anna Ansell, Christopher Sackmann, Harald Lund, Robert A Harris, Martin Hallbeck, Camilla Nilsberth
Neuroinflammation plays an influential role in Alzheimer's disease (AD), although the mechanisms underlying this phenomenon remain largely unknown. Microglia are thought to be responsible for the majority of these effects and can be characterized into resting (M0), proinflammatory (M1), or anti-inflammatory (M2) functional phenotypes. We investigated the effects of conditioned macrophage media, as an analogue to microglia, on the transfer of oligomeric amyloid beta (oAβ) between differentiated SH-SY5Y cells...
December 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28951447/experience-dependent-synaptic-plasticity-in-v1-occurs-without-microglial-cx3cr1
#15
Rachel W Schecter, Erin E Maher, Christina A Welsh, Beth Stevens, Alev Erisir, Mark F Bear
Brief monocular deprivation (MD) shifts ocular dominance and reduces the density of thalamic synapses in layer 4 of the mouse primary visual cortex (V1). We found that microglial lysosome content is also increased as a result of MD. Previous studies have shown that the microglial fractalkine receptor CX3CR1 is involved in synaptic development and hippocampal plasticity. We therefore tested the hypothesis that neuron-to-microglial communication via CX3CR1 is an essential component of visual cortical development and plasticity in male mice...
November 1, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28923083/prevention-of-c5ar1-signaling-delays-microglial-inflammatory-polarization-favors-clearance-pathways-and-suppresses-cognitive-loss
#16
Michael X Hernandez, Shan Jiang, Tracy A Cole, Shu-Hui Chu, Maria I Fonseca, Melody J Fang, Lindsay A Hohsfield, Maria D Torres, Kim N Green, Rick A Wetsel, Ali Mortazavi, Andrea J Tenner
BACKGROUND: Pharmacologic inhibition of C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, suppressed pathology and cognitive deficits in Alzheimer's disease (AD) mouse models. To validate that the effect of the antagonist was specifically via C5aR1 inhibition, mice lacking C5aR1 were generated and compared in behavior and pathology. In addition, since C5aR1 is primarily expressed on cells of the myeloid lineage, and only to a lesser extent on endothelial cells and neurons in brain, gene expression in microglia isolated from adult brain at multiple ages was compared across all genotypes...
September 18, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28904096/ripk1-mediates-a-disease-associated-microglial-response-in-alzheimer-s-disease
#17
Dimitry Ofengeim, Sonia Mazzitelli, Yasushi Ito, Judy Park DeWitt, Lauren Mifflin, Chengyu Zou, Sudeshna Das, Xian Adiconis, Hongbo Chen, Hong Zhu, Michelle A Kelliher, Joshua Z Levin, Junying Yuan
Dysfunction of microglia is known to play an important role in Alzheimer's disease (AD). Here, we investigated the role of RIPK1 in microglia mediating the pathogenesis of AD. RIPK1 is highly expressed by microglial cells in human AD brains. Using the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model, we found that inhibition of RIPK1, using both pharmacological and genetic means, reduced amyloid burden, the levels of inflammatory cytokines, and memory deficits. Furthermore, inhibition of RIPK1 promoted microglial degradation of Aβ in vitro...
October 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28866823/neuroprotective-effects-of-baicalein-on-acrolein-induced-neurotoxicity-in-the-nigrostriatal-dopaminergic-system-of-rat-brain
#18
Wei-Zhong Zhao, Hsiang-Tsui Wang, Hui-Ju Huang, Yu-Li Lo, Anya Maan-Yuh Lin
Elevated levels of acrolein, an α,β-unsaturated aldehyde are detected in the brain of patients with Parkinson's disease (PD). In the present study, the neuroprotective effect of baicalein (a phenolic flavonoid in the dried root of Scutellaria baicalensis Georgi) on acrolein-induced neurodegeneration of nigrostriatal dopaminergic system was investigated using local infusion of acrolein in the substantia nigra (SN) of rat brain. Systemic administration of baicalein (30 mg/kg, i.p.) significantly attenuated acrolein-induced elevations in 4-hydroxy-2-noneal (a product of lipid peroxidation), N-(3-formyl-3,4-dehydropiperidino)lysine (a biomarker of acrolein-conjugated proteins), and heme-oxygenase-1 levels (a redox-regulated protein) in the infused SN, indicating that baicalein inhibited acrolein-induced oxidative stress and protein conjugation...
September 2, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28827786/excess-%C3%AE-synuclein-compromises-phagocytosis-in-ipsc-derived-macrophages
#19
Walther Haenseler, Federico Zambon, Heyne Lee, Jane Vowles, Federica Rinaldi, Galbha Duggal, Henry Houlden, Katrina Gwinn, Selina Wray, Kelvin C Luk, Richard Wade-Martins, William S James, Sally A Cowley
To examine the pathogenic role of α-synuclein (αS) in Parkinson's Disease, we have generated induced Pluripotent Stem Cell lines from early onset Parkinson's Disease patients with SNCA A53T and SNCA Triplication mutations, and in this study have differentiated them to PSC-macrophages (pMac), which recapitulate many features of their brain-resident cousins, microglia. We show that SNCA Triplication pMac, but not A53T pMac, have significantly increased intracellular αS versus controls and release significantly more αS to the medium...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28776681/another-piece-in-the-progranulin-puzzle-special-binding-between-progranulin-and-prosaposin-creates-additional-lysosomal-access-an-editorial-comment-for-the-interaction-between-progranulin-and-prosaposin-is-mediated-by-granulins-and-the-linker-region-between
#20
EDITORIAL
Philip Van Damme
Loss-of-function mutations in the gene encoding the growth factor progranulin cause degeneration of the ageing brain in a dose-dependent manner. While heterozygous mutations result in adult onset frontotemporal dementia, the much rarer homozygous null mutations cause an early onset lysosomal storage disorder. A better understanding of the biology of progranulin in the central nervous system is needed to find solutions for these incurable diseases. This Editorial highlights a study by Zhou et al. in the current issue of the Journal of Neurochemistry, in which the authors provide data that are a step towards this goal...
October 2017: Journal of Neurochemistry
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