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Microglia and lysosome

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https://www.readbyqxmd.com/read/29025968/activation-of-ampk-mtorc1-mediated-autophagy-by-metformin-reverses-clk1-deficiency-sensitized-dopaminergic-neuronal-death
#1
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 explored the direct effect of Clk1 on dopaminergic neuronal survival. We demonstrated that Clk1 deficiency inhibited dopaminergic neuronal autophagy in cultured MN9D dopaminergic neurons and in SNc of Clk+/- mutant mice and consequently sensitized dopaminergic neuron damage and behavioral defects...
October 12, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28986232/rifampicin-inhibits-rotenone-induced-microglial-inflammation-via-enhancement-of-autophagy
#2
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
#3
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...
September 1, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28951447/experience-dependent-synaptic-plasticity-in-v1-occurs-without-microglial-cx3cr1
#4
Rachel W Schecter, Erin E Maher, Christina A Welsh, Beth Stevens, Alev Erisir, Mark F Bear
Brief monocular deprivation (MD) shifts ocular dominance (OD) and reduces the density of thalamic synapses in layer 4 of 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...
September 26, 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
#5
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
#6
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...
September 13, 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
#7
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
#8
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
#9
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
https://www.readbyqxmd.com/read/28769785/amyloid-%C3%AE-induced-redistribution-of-transcriptional-factor-eb-and-lysosomal-dysfunction-in-primary-microglial-cells
#10
Xingzhi Guo, Peng Tang, Li Chen, Peng Liu, Chen Hou, Xin Zhang, Yue Liu, Li Chong, Xiaoqing Li, Rui Li
Impaired clearance of Amyloid β (Aβ) by microglia in the brain may be associated with the senile plaque formation, a pathological hallmark relevant to Alzheimer's disease. Microglial cells in the brain are not able to efficiently degrade Aβ, suggesting that microglial lysosome impairment may occur. However, the mechanism of Aβ-induced impairment of microglia remains poorly understood. We observed the effects of Aβ on the trafficking of nuclear transcriptional factor EB (TFEB), a master regulator of lysosome biogenesis, and the expression of a downstream osteoporosis-associated transmembrane protein 1 (OSTM1), a vital molecule involved in lysosome acidification in primary microglial cells...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28689984/local-cues-establish-and-maintain-region-specific-phenotypes-of-basal-ganglia-microglia
#11
Lindsay M De Biase, Kornel E Schuebel, Zachary H Fusfeld, Kamwing Jair, Isobel A Hawes, Raffaello Cimbro, Hai-Ying Zhang, Qing-Rong Liu, Hui Shen, Zheng-Xiong Xi, David Goldman, Antonello Bonci
Microglia play critical roles in tissue homeostasis and can also modulate neuronal function and synaptic connectivity. In contrast to astrocytes and oligodendrocytes, which arise from multiple progenitor pools, microglia arise from yolk sac progenitors and are widely considered to be equivalent throughout the CNS. However, little is known about basic properties of deep brain microglia, such as those within the basal ganglia (BG). Here, we show that microglial anatomical features, lysosome content, membrane properties, and transcriptomes differ significantly across BG nuclei...
July 19, 2017: Neuron
https://www.readbyqxmd.com/read/28687233/overview-of-immune-abnormalities-in-lysosomal-storage-disorders
#12
REVIEW
Donato Rigante, Clelia Cipolla, Umberto Basile, Francesca Gulli, Maria Cristina Savastano
The critical relevance of the lysosomal compartment for normal cellular function can be proved by numbering the clinical phenotypes that arise in lysosomal storage disorders (LSDs), a group of around 70 different monogenic autosomal or X-linked syndromes, caused by specific lysosomal enzyme deficiencies: all LSDs are characterized by progressive accumulation of heterogeneous biologic materials in the lysosomes of various parts of the body such as viscera, skeleton, skin, heart, and central nervous system. At least a fraction of LSDs has been associated with mixed abnormalities involving the immune system, while some patients with LSDs may result more prone to autoimmune phenomena...
August 2017: Immunology Letters
https://www.readbyqxmd.com/read/28623605/cathepsin-c-aggravates-neuroinflammation-involved-in-disturbances-of-behaviour-and-neurochemistry-in-acute-and-chronic-stress-induced-murine-model-of-depression
#13
Yanli Zhang, Kai Fan, Yanna Liu, Gang Liu, Xiaohan Yang, Jianmei Ma
Major depression has been interpreted as an inflammatory disease characterized by cell-mediated immune activation, which is generally triggered by various stresses. Microglia has been thought to be the cellular link between inflammation and depression-like behavioural alterations. The expression of cathepsin C (Cat C), a lysosomal proteinase, is predominantly induced in microglia in neuroinflammation. However, little is known about the role of Cat C in pathophysiology of depression. In the present study, Cat C transgenic mice and wild type mice were subjected to an intraperitoneal injection of LPS (0...
June 16, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28623134/dysfunction-in-diurnal-synaptic-responses-and-social-behavior-abnormalities-in-cathepsin-s-deficient-mice
#14
Fumiko Takayama, Xinwen Zhang, Yoshinori Hayashi, Zhou Wu, Hiroshi Nakanishi
The expression of cathepsin S (CatS), a microglia-specific lysosomal cysteine protease in the brain, is regulated by the intrinsic microglial circadian clock. We herein report that the diurnal variation of evoked synaptic responses of cortical neurons disappeared in cathepsin S-deficient (CatS(-/-)) mice. The dendritic spine density of the cortical neurons was significantly reduced by incubation with a recombinant CatS. Furthermore, CatS(-/-) mice exhibited impaired social interaction and social novelty recognition in the three-chamber test...
August 19, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28597061/progressive-accumulation-of-autofluorescent-granules-in-macrophages-in-rat-striatum-after-systemic-3-nitropropionic-acid-a-correlative-light-and-electron-microscopic-study
#15
Tae-Ryong Riew, Hong Lim Kim, Jeong-Heon Choi, Xuyan Jin, Yoo-Jin Shin, Mun-Yong Lee
A variety of tissue biomolecules and intracellular structures are known to be autofluorescent. However, autofluorescent signals in brain tissues often confound analysis of the fluorescent markers used for immunohistochemistry. While investigating tissue and cellular pathologies induced by 3-nitropropionic acid, a mitochondrial toxin selective for striatal neurons, we encountered many autofluorescent signals confined to the lesion core. These structures were excited by blue (wavelength = 488 nm) and yellow-orange (555 nm), but not by red (639 nm) or violet (405 nm) lasers, indicating that this autofluorescence overlaps with the emission spectra of commonly used fluorophores...
June 9, 2017: Histochemistry and Cell Biology
https://www.readbyqxmd.com/read/28485547/pseudoginsenoside-f11-attenuates-cerebral-ischemic-injury-by%C3%A2-alleviating-autophagic-lysosomal-defects
#16
Yue-Yang Liu, Tian-Yu Zhang, Xue Xue, Dong-Mei Liu, Hao-Tian Zhang, Lin-Lin Yuan, Ying-Lu Liu, Han-Lin Yang, Shi-Bo Sun, Cheng Zhang, He-Song Xu, Chun-Fu Wu, Jing-Yu Yang
AIMS: Pseudoginsenoside-F11 (PF11), an ocotillol-type ginsenoside, has been reported to exert wide-ranging neuroprotective properties. The aim of this study was to investigate the effect and potential mechanisms of PF11 on the autophagic/lysosomal pathway following ischemic stroke. METHODS: Male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (pMCAO). Cerebral ischemia outcome, TUNEL staining, Fluoro-Jade B staining were carried out 24 hours poststroke...
July 2017: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/28479389/involvement-of-progranulin-in-modulating-neuroinflammatory-responses-but-not-neurogenesis-in-the-hippocampus-of-aged-mice
#17
Yanbo Ma, Takashi Matsuwaki, Keitaro Yamanouchi, Masugi Nishihara
It is well established that adult neurogenesis in the hippocampus declines with age. Our previous studies have suggested that progranulin (PGRN) has a facilitative effect on hippocampal neurogenesis. We have also shown that PGRN plays a role in suppressing excessive neuroinflammatory responses in the cortex and thalamus after brain injury and aging, respectively. However, the roles of PGRN in modulating neurogenesis and neuroinflammatory responses in the hippocampus of aged animals are not yet understood. In the present study, we investigated neurogenesis and neuroinflammation-related responses in the hippocampus of young (15-week-old) and old (135-week-old) wild-type and PGRN-deficient male mice...
September 2017: Experimental Gerontology
https://www.readbyqxmd.com/read/28476637/the-critical-role-of-nramp1-in-degrading-%C3%AE-synuclein-oligomers-in-microglia-under-iron-overload-condition
#18
Kuo-Chen Wu, Horng-Huei Liou, Yu-Han Kao, Chih-Yu Lee, Chun-Jung Lin
Oligomeric α-synuclein is a key mediator in the pathogenesis of Parkinson's disease (PD) and is mainly cleared by autophagy-lysosomal pathway, whose dysfunction results in the accumulation and cell-to-cell transmission of α-synuclein. In this study, concomitant with the accumulation of iron and oligomeric α-synuclein, higher expression of a lysosomal iron transporter, natural resistance-associated macrophage protein-1 (Nramp1), was observed in microglia in post-mortem striatum of sporadic PD patients. Using Nramp1-deficient macrophage (RAW264...
May 2, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28387679/orexin-impairs-the-phagocytosis-and-degradation-of-amyloid-%C3%AE-fibrils-by-microglial-cells
#19
Hoyoung An, Mi-Hyang Cho, Dong-Hou Kim, Seockhoon Chung, Seung-Yong Yoon
BACKGROUND: Intracranial accumulation of amyloid-β (Aβ) is a characteristic finding of Alzheimer's disease (AD). It is thought to be the result of Aβ overproduction by neurons and impaired clearance by several systems, including degradation by microglia. Sleep disturbance is now considered a risk factor for AD, but studies focusing on how sleep modulates microglial handling of Aβ have been scarce. OBJECTIVE: To determine whether phagocytosis and degradation of extracellular Aβ fibrils by BV2 microglial cells were impaired by treatment with orexin-A/B, a major modulator of the sleep-wake cycle, which may mimic sleep deprivation conditions...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28379303/restoring-neuronal-progranulin-reverses-deficits-in-a-mouse-model-of-frontotemporal-dementia
#20
Andrew E Arrant, Anthony J Filiano, Daniel E Unger, Allen H Young, Erik D Roberson
Loss-of-function mutations in progranulin (GRN), a secreted glycoprotein expressed by neurons and microglia, are a common autosomal dominant cause of frontotemporal dementia, a neurodegenerative disease commonly characterized by disrupted social and emotional behaviour. GRN mutations are thought to cause frontotemporal dementia through progranulin haploinsufficiency, therefore, boosting progranulin expression from the intact allele is a rational treatment strategy. However, this approach has not been tested in an animal model of frontotemporal dementia and it is unclear if boosting progranulin could correct pre-existing deficits...
March 29, 2017: Brain: a Journal of Neurology
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