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TREM2 microglia

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https://www.readbyqxmd.com/read/28987033/trem2-expression-in-the-human-brain-a-marker-of-monocyte-recruitment
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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/28894284/trem2-promotes-a%C3%AE-phagocytosis-by-upregulating-c-ebp%C3%AE-dependent-cd36-expression-in-microglia
#7
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
#8
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
#9
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
#10
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/28769786/mild-inflammatory-profile-without-gliosis-in-the-c-rel-deficient-mouse-modeling-a-late-onset-parkinsonism
#11
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
#12
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/28714976/rare-coding-variants-in-plcg2-abi3-and-trem2-implicate-microglial-mediated-innate-immunity-in-alzheimer-s-disease
#13
Rebecca Sims, Sven J van der Lee, Adam C Naj, Céline Bellenguez, Nandini Badarinarayan, Johanna Jakobsdottir, Brian W Kunkle, Anne Boland, Rachel Raybould, Joshua C Bis, Eden R Martin, Benjamin Grenier-Boley, Stefanie Heilmann-Heimbach, Vincent Chouraki, Amanda B Kuzma, Kristel Sleegers, Maria Vronskaya, Agustin Ruiz, Robert R Graham, Robert Olaso, Per Hoffmann, Megan L Grove, Badri N Vardarajan, Mikko Hiltunen, Markus M Nöthen, Charles C White, Kara L Hamilton-Nelson, Jacques Epelbaum, Wolfgang Maier, Seung-Hoan Choi, Gary W Beecham, Cécile Dulary, Stefan Herms, Albert V Smith, Cory C Funk, Céline Derbois, Andreas J Forstner, Shahzad Ahmad, Hongdong Li, Delphine Bacq, Denise Harold, Claudia L Satizabal, Otto Valladares, Alessio Squassina, Rhodri Thomas, Jennifer A Brody, Liming Qu, Pascual Sánchez-Juan, Taniesha Morgan, Frank J Wolters, Yi Zhao, Florentino Sanchez Garcia, Nicola Denning, Myriam Fornage, John Malamon, Maria Candida Deniz Naranjo, Elisa Majounie, Thomas H Mosley, Beth Dombroski, David Wallon, Michelle K Lupton, Josée Dupuis, Patrice Whitehead, Laura Fratiglioni, Christopher Medway, Xueqiu Jian, Shubhabrata Mukherjee, Lina Keller, Kristelle Brown, Honghuang Lin, Laura B Cantwell, Francesco Panza, Bernadette McGuinness, Sonia Moreno-Grau, Jeremy D Burgess, Vincenzo Solfrizzi, Petra Proitsi, Hieab H Adams, Mariet Allen, Davide Seripa, Pau Pastor, L Adrienne Cupples, Nathan D Price, Didier Hannequin, Ana Frank-García, Daniel Levy, Paramita Chakrabarty, Paolo Caffarra, Ina Giegling, Alexa S Beiser, Vilmantas Giedraitis, Harald Hampel, Melissa E Garcia, Xue Wang, Lars Lannfelt, Patrizia Mecocci, Gudny Eiriksdottir, Paul K Crane, Florence Pasquier, Virginia Boccardi, Isabel Henández, Robert C Barber, Martin Scherer, Lluis Tarraga, Perrie M Adams, Markus Leber, Yuning Chen, Marilyn S Albert, Steffi Riedel-Heller, Valur Emilsson, Duane Beekly, Anne Braae, Reinhold Schmidt, Deborah Blacker, Carlo Masullo, Helena Schmidt, Rachelle S Doody, Gianfranco Spalletta, W T Longstreth Jr, Thomas J Fairchild, Paola Bossù, Oscar L Lopez, Matthew P Frosch, Eleonora Sacchinelli, Bernardino Ghetti, Qiong Yang, Ryan M Huebinger, Frank Jessen, Shuo Li, M Ilyas Kamboh, John Morris, Oscar Sotolongo-Grau, Mindy J Katz, Chris Corcoran, Melanie Dunstan, Amy Braddel, Charlene Thomas, Alun Meggy, Rachel Marshall, Amy Gerrish, Jade Chapman, Miquel Aguilar, Sarah Taylor, Matt Hill, Mònica Díez Fairén, Angela Hodges, Bruno Vellas, Hilkka Soininen, Iwona Kloszewska, Makrina Daniilidou, James Uphill, Yogen Patel, Joseph T Hughes, Jenny Lord, James Turton, Annette M Hartmann, Roberta Cecchetti, Chiara Fenoglio, Maria Serpente, Marina Arcaro, Carlo Caltagirone, Maria Donata Orfei, Antonio Ciaramella, Sabrina Pichler, Manuel Mayhaus, Wei Gu, Alberto Lleó, Juan Fortea, Rafael Blesa, Imelda S Barber, Keeley Brookes, Chiara Cupidi, Raffaele Giovanni Maletta, David Carrell, Sandro Sorbi, Susanne Moebus, Maria Urbano, Alberto Pilotto, Johannes Kornhuber, Paolo Bosco, Stephen Todd, David Craig, Janet Johnston, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Nick C Fox, John Hardy, Roger L Albin, Liana G Apostolova, Steven E Arnold, Sanjay Asthana, Craig S Atwood, Clinton T Baldwin, Lisa L Barnes, Sandra Barral, Thomas G Beach, James T Becker, Eileen H Bigio, Thomas D Bird, Bradley F Boeve, James D Bowen, Adam Boxer, James R Burke, Jeffrey M Burns, Joseph D Buxbaum, Nigel J Cairns, Chuanhai Cao, Chris S Carlson, Cynthia M Carlsson, Regina M Carney, Minerva M Carrasquillo, Steven L Carroll, Carolina Ceballos Diaz, Helena C Chui, David G Clark, David H Cribbs, Elizabeth A Crocco, Charles DeCarli, Malcolm Dick, Ranjan Duara, Denis A Evans, Kelley M Faber, Kenneth B Fallon, David W Fardo, Martin R Farlow, Steven Ferris, Tatiana M Foroud, Douglas R Galasko, Marla Gearing, Daniel H Geschwind, John R Gilbert, Neill R Graff-Radford, Robert C Green, John H Growdon, Ronald L Hamilton, Lindy E Harrell, Lawrence S Honig, Matthew J Huentelman, Christine M Hulette, Bradley T Hyman, Gail P Jarvik, Erin Abner, Lee-Way Jin, Gyungah Jun, Anna Karydas, Jeffrey A Kaye, Ronald Kim, Neil W Kowall, Joel H Kramer, Frank M LaFerla, James J Lah, James B Leverenz, Allan I Levey, Ge Li, Andrew P Lieberman, Kathryn L Lunetta, Constantine G Lyketsos, Daniel C Marson, Frank Martiniuk, Deborah C Mash, Eliezer Masliah, Wayne C McCormick, Susan M McCurry, Andrew N McDavid, Ann C McKee, Marsel Mesulam, Bruce L Miller, Carol A Miller, Joshua W Miller, John C Morris, Jill R Murrell, Amanda J Myers, Sid O'Bryant, John M Olichney, Vernon S Pankratz, Joseph E Parisi, Henry L Paulson, William Perry, Elaine Peskind, Aimee Pierce, Wayne W Poon, Huntington Potter, Joseph F Quinn, Ashok Raj, Murray Raskind, Barry Reisberg, Christiane Reitz, John M Ringman, Erik D Roberson, Ekaterina Rogaeva, Howard J Rosen, Roger N Rosenberg, Mark A Sager, Andrew J Saykin, Julie A Schneider, Lon S Schneider, William W Seeley, Amanda G Smith, Joshua A Sonnen, Salvatore Spina, Robert A Stern, Russell H Swerdlow, Rudolph E Tanzi, Tricia A Thornton-Wells, John Q Trojanowski, Juan C Troncoso, Vivianna M Van Deerlin, Linda J Van Eldik, Harry V Vinters, Jean Paul Vonsattel, Sandra Weintraub, Kathleen A Welsh-Bohmer, Kirk C Wilhelmsen, Jennifer Williamson, Thomas S Wingo, Randall L Woltjer, Clinton B Wright, Chang-En Yu, Lei Yu, Fabienne Garzia, Feroze Golamaully, Gislain Septier, Sebastien Engelborghs, Rik Vandenberghe, Peter P De Deyn, Carmen Muñoz Fernadez, Yoland Aladro Benito, Hakan Thonberg, Charlotte Forsell, Lena Lilius, Anne Kinhult-Stählbom, Lena Kilander, RoseMarie Brundin, Letizia Concari, Seppo Helisalmi, Anne Maria Koivisto, Annakaisa Haapasalo, Vincent Dermecourt, Nathalie Fievet, Olivier Hanon, Carole Dufouil, Alexis Brice, Karen Ritchie, Bruno Dubois, Jayanadra J Himali, C Dirk Keene, JoAnn Tschanz, Annette L Fitzpatrick, Walter A Kukull, Maria Norton, Thor Aspelund, Eric B Larson, Ron Munger, Jerome I Rotter, Richard B Lipton, María J Bullido, Albert Hofman, Thomas J Montine, Eliecer Coto, Eric Boerwinkle, Ronald C Petersen, Victoria Alvarez, Fernando Rivadeneira, Eric M Reiman, Maura Gallo, Christopher J O'Donnell, Joan S Reisch, Amalia Cecilia Bruni, Donald R Royall, Martin Dichgans, Mary Sano, Daniela Galimberti, Peter St George-Hyslop, Elio Scarpini, Debby W Tsuang, Michelangelo Mancuso, Ubaldo Bonuccelli, Ashley R Winslow, Antonio Daniele, Chuang-Kuo Wu, Oliver Peters, Benedetta Nacmias, Matthias Riemenschneider, Reinhard Heun, Carol Brayne, David C Rubinsztein, Jose Bras, Rita Guerreiro, Ammar Al-Chalabi, Christopher E Shaw, John Collinge, David Mann, Magda Tsolaki, Jordi Clarimón, Rebecca Sussams, Simon Lovestone, Michael C O'Donovan, Michael J Owen, Timothy W Behrens, Simon Mead, Alison M Goate, Andre G Uitterlinden, Clive Holmes, Carlos Cruchaga, Martin Ingelsson, David A Bennett, John Powell, Todd E Golde, Caroline Graff, Philip L De Jager, Kevin Morgan, Nilufer Ertekin-Taner, Onofre Combarros, Bruce M Psaty, Peter Passmore, Steven G Younkin, Claudine Berr, Vilmundur Gudnason, Dan Rujescu, Dennis W Dickson, Jean-François Dartigues, Anita L DeStefano, Sara Ortega-Cubero, Hakon Hakonarson, Dominique Campion, Merce Boada, John Keoni Kauwe, Lindsay A Farrer, Christine Van Broeckhoven, M Arfan Ikram, Lesley Jones, Jonathan L Haines, Christophe Tzourio, Lenore J Launer, Valentina Escott-Price, Richard Mayeux, Jean-François Deleuze, Najaf Amin, Peter A Holmans, Margaret A Pericak-Vance, Philippe Amouyel, Cornelia M van Duijn, Alfredo Ramirez, Li-San Wang, Jean-Charles Lambert, Sudha Seshadri, Julie Williams, Gerard D Schellenberg
We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10(-4)) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10(-8)) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p...
September 2017: Nature Genetics
https://www.readbyqxmd.com/read/28683563/modulation-of-hematopoietic-lineage-specification-impacts-trem2-expression-in-microglia-like-cells-derived-from-human-stem-cells
#14
Peter J Amos, Susan Fung, Amanda Case, Jerusalem Kifelew, Leah Osnis, Carole L Smith, Kevin Green, Alipi Naydenov, Macarena Aloi, Jesse J Hubbard, Aravind Ramakrishnan, Gwenn A Garden, Suman Jayadev
Microglia are the primary innate immune cell type in the brain, and their dysfunction has been linked to a variety of central nervous system disorders. Human microglia are extraordinarily difficult to obtain for experimental investigation, limiting our ability to study the impact of human genetic variants on microglia functions. Previous studies have reported that microglia-like cells can be derived from human monocytes or pluripotent stem cells. Here, we describe a reproducible relatively simple method for generating microglia-like cells by first deriving embryoid body mesoderm followed by exposure to microglia relevant cytokines...
July 2017: ASN Neuro
https://www.readbyqxmd.com/read/28680398/trem2-dap12-complex-regulates-inflammatory-responses-in-microglia-via-the-jnk-signaling-pathway
#15
Li Zhong, Zhen-Lian Zhang, Xinxiu Li, Chunyan Liao, Pengfei Mou, Tingting Wang, Zongqi Wang, Zhe Wang, Min Wei, Huaxi Xu, Guojun Bu, Xiao-Fen Chen
DNAX-activating protein of 12 kDa (DAP12) is a signaling adapter protein expressed in cells that participate in innate immune responses. By pairing with different triggering receptors expressed on myeloid cell (TREM) proteins, DAP12 can mediate both positive and negative cellular responses. In particular, TREM1 acts as an amplifier of the immune response, while TREM2 functions as a negative regulator. TREM2 has also been shown to stimulate the phagocytosis of apoptotic neurons and define the barrier function in microglia...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28628896/cholinergic-neuron-gene-expression-differences-captured-by-translational-profiling-in-a-mouse-model-of-alzheimer-s-disease
#16
Paul M McKeever, TaeHyung Kim, Andrew R Hesketh, Laura MacNair, Denise Miletic, Giorgio Favrin, Stephen G Oliver, Zhaolei Zhang, Peter St George-Hyslop, Janice Robertson
Cholinergic neurotransmission is impaired in Alzheimer's disease (AD), and loss of basal forebrain cholinergic neurons is a key component of disease pathogenicity and symptomatology. To explore the molecular basis of this cholinergic dysfunction, we paired translating ribosome affinity purification (TRAP) with RNA sequencing (TRAP-Seq) to identify the actively translating mRNAs in anterior forebrain cholinergic neurons in the TgCRND8 mouse model of AD. Bioinformatic analyses revealed the downregulation of 67 of 71 known cholinergic-related transcripts, consistent with cholinergic neuron dysfunction in TgCRND8 mice, as well as transcripts related to oxidative phosphorylation, neurotrophins, and ribosomal processing...
September 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28612290/deficiency-of-tyrobp-an-adapter-protein-for-trem2-and-cr3-receptors-is-neuroprotective-in-a-mouse-model-of-early-alzheimer-s-pathology
#17
Jean-Vianney Haure-Mirande, Mickael Audrain, Tomas Fanutza, Soong Ho Kim, William L Klein, Charles Glabe, Ben Readhead, Joel T Dudley, Robert D Blitzer, Minghui Wang, Bin Zhang, Eric E Schadt, Sam Gandy, Michelle E Ehrlich
Conventional genetic approaches and computational strategies have converged on immune-inflammatory pathways as key events in the pathogenesis of late onset sporadic Alzheimer's disease (LOAD). Mutations and/or differential expression of microglial specific receptors such as TREM2, CD33, and CR3 have been associated with strong increased risk for developing Alzheimer's disease (AD). DAP12 (DNAX-activating protein 12)/TYROBP, a molecule localized to microglia, is a direct partner/adapter for TREM2, CD33, and CR3...
June 13, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28602351/a-unique-microglia-type-associated-with-restricting-development-of-alzheimer-s-disease
#18
Hadas Keren-Shaul, Amit Spinrad, Assaf Weiner, Orit Matcovitch-Natan, Raz Dvir-Szternfeld, Tyler K Ulland, Eyal David, Kuti Baruch, David Lara-Astaiso, Beata Toth, Shalev Itzkovitz, Marco Colonna, Michal Schwartz, Ido Amit
Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells...
June 15, 2017: Cell
https://www.readbyqxmd.com/read/28601603/enhanced-classical-complement-pathway-activation-and-altered-phagocytosis-signaling-molecules-in-human-epilepsy
#19
Season K Wyatt, Thomas Witt, Nicholas M Barbaro, Aaron A Cohen-Gadol, Amy L Brewster
Microglia-mediated neuroinflammation is widely associated with seizures and epilepsy. Although microglial cells are professional phagocytes, less is known about the status of this phenotype in epilepsy. Recent evidence supports that phagocytosis-associated molecules from the classical complement (C1q-C3) play novel roles in microglia-mediated synaptic pruning. Interestingly, in human and experimental epilepsy, altered mRNA levels of complement molecules were reported. Therefore, to identify a potential role for complement and microglia in the synaptodendritic pathology of epilepsy, we determined the protein levels of classical complement proteins (C1q-C3) along with other phagocytosis signaling molecules in human epilepsy...
September 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28592261/trem2-protects-against-cerebral-ischemia-reperfusion-injury
#20
Rong Wu, Xiangpen Li, Pengfei Xu, Likui Huang, Jinping Cheng, Xiaolong Huang, Jingru Jiang, Long-Jun Wu, Yamei Tang
Although post-ischemic inflammation induced by the innate immune response is considered an essential step in the progression of cerebral ischemia injury, the role of triggering receptor expressed on myeloid cells 2 (TREM2) in the pathogenesis of ischemic stroke remains to be elucidated. Here, we found that the transcriptional and post-transcriptional levels of TREM2 were increased in cultured primary microglia after oxygen-glucose deprivation and reoxygenation and in the ischemic penumbra of the cerebral cortex after middle cerebral artery occlusion (MCAO) and reperfusion in mice...
June 7, 2017: Molecular Brain
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