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https://www.readbyqxmd.com/read/29040522/behavioral-and-transcriptomic-analysis-of-trem2-null-mice-not-all-knockout-mice-are-created-equal
#1
Silvia S Kang, Aishe Kurti, Kelsey E Baker, Chia-Chen Liu, Marco Colonna, Jason D Ulrich, David M Holtzman, Guojun Bu, John D Fryer
It is clear that innate immune system status is altered in numerous neurodegenerative diseases. Human genetic studies have demonstrated that Triggering Receptor Expressed in Myeloid cells 2 (TREM2) coding variants have a strong association with Alzheimer's disease (AD) and other neurodegenerative diseases. To more thoroughly understand the impact of TREM2 in vivo, we studied the behavioral and cognitive functions of wild-type (WT) and Trem2-/- (KO) mice during basal conditions and brain function in the context of innate immune stimulation with peripherally administered lipopolysaccharide (LPS)...
October 11, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29037207/trem2-deficiency-exacerbates-tau-pathology-through-dysregulated-kinase-signaling-in-a-mouse-model-of-tauopathy
#2
Shane M Bemiller, Tyler J McCray, Kevin Allan, Shane V Formica, Guixiang Xu, Gina Wilson, Olga N Kokiko-Cochran, Samuel D Crish, Cristian A Lasagna-Reeves, Richard M Ransohoff, Gary E Landreth, Bruce T Lamb
BACKGROUND: Genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) confer increased risk of developing late-onset Alzheimer's Disease (LOAD) and other neurodegenerative disorders. Recent studies provided insight into the multifaceted roles of TREM2 in regulating extracellular β-amyloid (Aβ) pathology, myeloid cell accumulation, and inflammation observed in AD, yet little is known regarding the role of TREM2 in regulating intracellular microtubule associated protein tau (MAPT; tau) pathology in neurodegenerative diseases and in AD, in particular...
October 16, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29036448/il6-secretion-from-alternatively-activated-macrophages-promotes-the-migration-of-endometriotic-epithelial-cells
#3
Jeong-Hwa Woo, Yeong-In Yang, Ji-Hye Ahn, Youn Seok Choi, Jung-Hye Choi
Accumulating evidence has suggested an interaction between endometriotic cells and macrophages in the endometriotic microenvironment and the potential role of this interaction in the pathogenesis of endometriosis. However, how endometriotic cells communicate with macrophages to influence their function is poorly understood. In the present study, we found that the mRNA expression and production of CC chemokine ligand 2 (CCL2) were much higher in human endometriotic epithelial cells (11Z and 12Z) than those in human endometrial epithelial cells (HES)...
October 4, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/29017955/triggering-receptor-expressed-on-myeloid-cells-2-trem-2-expression-tracks-with-m2-like-macrophage-activity-and-disease-severity-in-copd
#4
Derek E Byers, Kangyun Wu, Geoffrey Dang-Vu, Xiaohua Jin, Eugene Agapov, Xiaofeng Zhang, John T Battaile, Kenneth Schechtman, Roger Yusen, Richard A Pierce, Michael J Holtzman
BACKGROUND: Cell and animal models show a key role for Triggering Receptor Expressed on Myeloid Cells-2 (TREM-2) in chronic airway disease after viral infection but comparable evidence in humans still needs to be established. METHODS: Lung tissue samples were obtained from lung transplant recipients with GOLD Stage 4 COPD (n=16), non-transplantable donor lung tissues (n=10), and resected lung tissues from at-risk or GOLD Stage 1-4 patients (n=72) and were assessed for TREM-2 and TREM-1 mRNA, protein expression, and other markers of a type 2 immune response...
October 7, 2017: Chest
https://www.readbyqxmd.com/read/28987033/trem2-expression-in-the-human-brain-a-marker-of-monocyte-recruitment
#5
Marie Fahrenhold, Sonja Rakic, John Classey, Carol Brayne, Paul G Ince, James A R Nicoll, Delphine Boche
Mutation in the triggering receptor expressed on myeloid cells (TREM) 2 gene has been identified as a risk factor for several neurodegenerative diseases including Alzheimer's disease (AD). Experimental studies using animal models of AD have highlighted a number of functions associated with TREM2 and its expression by microglial cells. It has therefore been assumed that this is also the case in humans. However, there is very limited information concerning the cellular expression of TREM2 in the human brain. As part of investigations of microglia using post-mortem resources provided by the Medical Research Council Cognitive Function and Ageing Studies (MRC-CFAS), we immunostained the cerebral cortex of 299 participants for TREM2 using the Sigma antibody HPA010917 and compared with the macrophage/microglial markers Iba1 and CD68...
October 7, 2017: Brain Pathology
https://www.readbyqxmd.com/read/28978423/trem2-keeping-microglia-fit-during-good-times-and-bad
#6
Soyon Hong, Beth Stevens
Microglia are the macrophages of the brain and play an important role in Alzheimer's disease (AD). In Cell, Ulland et al. (2017) recently reported that mutations in TREM2, a protein implicated in AD, disrupt microglial energy state and function, thus sabotaging the microglia's ability to defend the brain against amyloid plaques.
October 3, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28930663/the-trem2-apoe-pathway-drives-the-transcriptional-phenotype-of-dysfunctional-microglia-in-neurodegenerative-diseases
#7
Susanne Krasemann, Charlotte Madore, Ron Cialic, Caroline Baufeld, Narghes Calcagno, Rachid El Fatimy, Lien Beckers, Elaine O'Loughlin, Yang Xu, Zain Fanek, David J Greco, Scott T Smith, George Tweet, Zachary Humulock, Tobias Zrzavy, Patricia Conde-Sanroman, Mar Gacias, Zhiping Weng, Hao Chen, Emily Tjon, Fargol Mazaheri, Kristin Hartmann, Asaf Madi, Jason D Ulrich, Markus Glatzel, Anna Worthmann, Joerg Heeren, Bogdan Budnik, Cynthia Lemere, Tsuneya Ikezu, Frank L Heppner, Vladimir Litvak, David M Holtzman, Hans Lassmann, Howard L Weiner, Jordi Ochando, Christian Haass, Oleg Butovsky
Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons...
September 19, 2017: Immunity
https://www.readbyqxmd.com/read/28930654/a-tale-of-two-genes-microglial-apoe-and-trem2
#8
Anna A Pimenova, Edoardo Marcora, Alison M Goate
Microglial cell function is implicated in the etiology of Alzheimer's disease by human genetics. In this issue of Immunity, Krasemann et al. (2017) describe a gene expression signature associated with an APOE- and TREM2-dependent response of microglia to brain tissue damage that accumulates in aging and disease, defining an axis that might be amenable to therapeutic targeting.
September 19, 2017: Immunity
https://www.readbyqxmd.com/read/28923481/adam17-is-the-main-sheddase-for-the-generation-of-human-triggering-receptor-expressed-in-myeloid-cells-htrem2-ectodomain-and-cleaves-trem2-after-histidine-157
#9
Dominik Feuerbach, Patrick Schindler, Carmen Barske, Stefanie Joller, Edwige Beng-Louka, Katie A Worringer, Sravya Kommineni, Ajamete Kaykas, Daniel J Ho, Chaoyang Ye, Karl Welzenbach, Gaelle Elain, Laurent Klein, Irena Brzak, Anis K Mir, Christopher J Farady, Reiner Aichholz, Simone Popp, Nathalie George, Ulf Neumann
Triggering receptor expressed in myeloid cells (TREM2) is a member of the immunoglobulin superfamily and is expressed in macrophages, dendritic cells, microglia, and osteoclasts. TREM2 plays a role in phagocytosis, regulates release of cytokine, contributes to microglia maintenance, and its ectodomain is shed from the cell surface. Here, the question was addressed at which position sheddases cleave TREM2 and what are the proteases involved in this process. Using both pharmacological and genetic approaches we report that the main protease contributing to the release of TREM2 ectodomain is ADAM17, (a disintegrin and metalloproteinase domain containing protein, also called TACE, TNFα converting enzyme) while ADAM10 plays a minor role...
September 18, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28912710/key-aging-associated-alterations-in-primary-microglia-response-to-beta-amyloid-stimulation
#10
Cláudia Caldeira, Carolina Cunha, Ana R Vaz, Ana S Falcão, Andreia Barateiro, Elsa Seixas, Adelaide Fernandes, Dora Brites
Alzheimer's disease (AD) is characterized by a progressive cognitive decline and believed to be driven by the self-aggregation of amyloid-β (Aβ) peptide into oligomers and fibrils that accumulate as senile plaques. It is widely accepted that microglia-mediated inflammation is a significant contributor to disease pathogenesis; however, different microglia phenotypes were identified along AD progression and excessive Aβ production was shown to dysregulate cell function. As so, the contribution of microglia to AD pathogenesis remains to be elucidated...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28900132/the-lipid-sensor-trem2-aggravates-disease-in-a-model-of-lcmv-induced-hepatitis
#11
Lindsay Kosack, Riem Gawish, Alexander Lercher, Bojan Vilagos, Anastasiya Hladik, Karin Lakovits, Anannya Bhattacharya, Christopher Schliehe, Ildiko Mesteri, Sylvia Knapp, Andreas Bergthaler
Lipid metabolism is increasingly being appreciated to affect immunoregulation, inflammation and pathology. In this study we found that mice infected with lymphocytic choriomeningitis virus (LCMV) exhibit global perturbations of circulating serum lipids. Mice lacking the lipid-sensing surface receptor triggering receptor expressed on myeloid cells 2 (Trem2 (-/-)) were protected from LCMV-induced hepatitis and showed improved virus control despite comparable virus-specific T cell responses. Non-hematopoietic expression of TREM2 was found to be responsible for aggravated hepatitis, indicating a novel role for TREM2 in the non-myeloid compartment...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28894284/trem2-promotes-a%C3%AE-phagocytosis-by-upregulating-c-ebp%C3%AE-dependent-cd36-expression-in-microglia
#12
Su-Man Kim, Bo-Ram Mun, Sun-Jun Lee, Yechan Joh, Hwa-Youn Lee, Kon-Young Ji, Ha-Rim Choi, Eun-Hee Lee, Eun-Mi Kim, Ji-Hye Jang, Hyeong-Woo Song, Inhee Mook-Jung, Won-Seok Choi, Hyung-Sik Kang
TREM2 plays a critical role in the alleviation of Alzheimer's disease by promoting Aβ phagocytosis by microglia, but the detailed molecular mechanism underlying TREM2-induced direct phagocytic activity of Aβ remains to be revealed. We found that learning and memory functions were improved in aged TREM2 TG mice, with the opposite effects in KO mice. The amount of phagocytosed Aβ was significantly reduced in the primary microglia of KO mice. CD36 expression in primary microglia was greater in TG than in WT mice but was substantially decreased in KO mice...
September 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28855301/trem2-shedding-by-cleavage-at-the-h157-s158-bond-is-accelerated-for-the-alzheimer-s-disease-associated-h157y-variant
#13
Peter Thornton, Jean Sevalle, Michael J Deery, Graham Fraser, Ye Zhou, Sara Ståhl, Elske H Franssen, Roger B Dodd, Seema Qamar, Beatriz Gomez Perez-Nievas, Louise Sc Nicol, Susanna Eketjäll, Jefferson Revell, Clare Jones, Andrew Billinton, Peter H St George-Hyslop, Iain Chessell, Damian C Crowther
We have characterised the proteolytic cleavage events responsible for the shedding of triggering receptor expressed on myeloid cells 2 (TREM2) from primary cultures of human macrophages, murine microglia and TREM2-expressing human embryonic kidney (HEK293) cells. In all cell types, a soluble 17 kDa N-terminal cleavage fragment was shed into the conditioned media in a constitutive process that is inhibited by G1254023X and metalloprotease inhibitors and siRNA targeting ADAM10. Inhibitors of serine proteases and matrix metalloproteinases 2/9, and ADAM17 siRNA did not block TREM2 shedding...
October 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28855300/an-alzheimer-associated-trem2-variant-occurs-at-the-adam-cleavage-site-and-affects-shedding-and-phagocytic-function
#14
Kai Schlepckow, Gernot Kleinberger, Akio Fukumori, Regina Feederle, Stefan F Lichtenthaler, Harald Steiner, Christian Haass
Sequence variations occurring in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) support an essential function of microglia and innate immunity in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. TREM2 matures within the secretory pathway, and its ectodomain is shed on the plasma membrane. Missense mutations in the immunoglobulin (Ig)-like domain such as p.T66M and p.Y38C retain TREM2 within the endoplasmic reticulum and reduce shedding as well as TREM2-dependent phagocytosis...
October 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28802038/trem2-maintains-microglial-metabolic-fitness-in-alzheimer-s-disease
#15
Tyler K Ulland, Wilbur M Song, Stanley Ching-Cheng Huang, Jason D Ulrich, Alexey Sergushichev, Wandy L Beatty, Alexander A Loboda, Yingyue Zhou, Nigel J Cairns, Amal Kambal, Ekaterina Loginicheva, Susan Gilfillan, Marina Cella, Herbert W Virgin, Emil R Unanue, Yaming Wang, Maxim N Artyomov, David M Holtzman, Marco Colonna
Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28789839/contribution-to-alzheimer-s-disease-risk-of-rare-variants-in-trem2-sorl1-and-abca7-in-1779-cases-and-1273-controls
#16
Céline Bellenguez, Camille Charbonnier, Benjamin Grenier-Boley, Olivier Quenez, Kilan Le Guennec, Gaël Nicolas, Ganesh Chauhan, David Wallon, Stéphane Rousseau, Anne Claire Richard, Anne Boland, Guillaume Bourque, Hans Markus Munter, Robert Olaso, Vincent Meyer, Adeline Rollin-Sillaire, Florence Pasquier, Luc Letenneur, Richard Redon, Jean-François Dartigues, Christophe Tzourio, Thierry Frebourg, Mark Lathrop, Jean-François Deleuze, Didier Hannequin, Emmanuelle Genin, Philippe Amouyel, Stéphanie Debette, Jean-Charles Lambert, Dominique Campion
We performed whole-exome and whole-genome sequencing in 927 late-onset Alzheimer disease (LOAD) cases, 852 early-onset AD (EOAD) cases, and 1273 controls from France. We assessed the evidence for gene-based association of rare variants with AD in 6 genes for which an association with such variants was previously claimed. When aggregating protein-truncating and missense-predicted damaging variants, we found exome-wide significant association between EOAD risk and rare variants in SORL1, TREM2, and ABCA7. No exome-wide significant signal was obtained in the LOAD sample, and significance of the order of 10(-6) was observed in the whole AD group for TREM2...
November 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28769786/mild-inflammatory-profile-without-gliosis-in-the-c-rel-deficient-mouse-modeling-a-late-onset-parkinsonism
#17
Vanessa Porrini, Mariana Mota, Edoardo Parrella, Arianna Bellucci, Marina Benarese, Lara Faggi, Paolo Tonin, Pier F Spano, Marina Pizzi
The impact of neuroinflammation and microglial activation to Parkinson's disease (PD) progression is still debated. Post-mortem analysis of PD brains has shown that neuroinflammation and microgliosis are key features of end-stage disease. However, microglia neuroimaging studies and evaluation of cerebrospinal fluid (CSF) cytokines in PD patients at earlier stages do not support the occurrence of a pronounced neuroinflammatory process. PD animal models recapitulating the motor and non-motor features of the disease, and the slow and progressive neuropathology, can be of great advantage in understanding whether and how neuroinflammation associates with the onset of symptoms and neuronal loss...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28768830/neurodegeneration-associated-mutant-trem2-proteins-abortively-cycle-between-the-er-and-er-golgi-intermediate-compartment
#18
Daniel W Sirkis, Renan E Aparicio, Randy Schekman
Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein expressed on microglia within the brain. Several rare mutations in TREM2 cause an early-onset form of neurodegeneration when inherited homozygously. Here we investigate how these mutations affect the intracellular transport of TREM2. We find that most pathogenic TREM2 mutant proteins fail to undergo normal maturation in the Golgi complex and show markedly reduced cell-surface expression. Prior research has suggested that two such mutants are retained in the endoplasmic reticulum (ER), but we find, using a cell-free coat protein complex II (COPII) vesicle budding reaction, that mutant TREM2 is exported efficiently from the ER...
October 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28768545/trem2-in-neurodegenerative-diseases
#19
REVIEW
Taylor R Jay, Victoria E von Saucken, Gary E Landreth
TREM2 variants have been identified as risk factors for Alzheimer's disease (AD) and other neurodegenerative diseases (NDDs). Because TREM2 encodes a receptor exclusively expressed on immune cells, identification of these variants conclusively demonstrates that the immune response can play an active role in the pathogenesis of NDDs. These TREM2 variants also confer the highest risk for developing Alzheimer's disease of any risk factor identified in nearly two decades, suggesting that understanding more about TREM2 function could provide key insights into NDD pathology and provide avenues for novel immune-related NDD biomarkers and therapeutics...
August 2, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28747390/%C3%AE-catenin-pathway-is-involved-in-trem2-mediated-microglial-survival
#20
Shadaan Zulfiqar, Gaye Tanriöver
No abstract text is available yet for this article.
July 26, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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