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https://www.readbyqxmd.com/read/29906661/loss-of-trem2-in-microglia-leads-to-widespread-disruption-of-cell-coexpression-networks-in-mouse-brain
#1
Guillermo Carbajosa, Karim Malki, Nathan Lawless, Hong Wang, John W Ryder, Eva Wozniak, Kristie Wood, Charles A Mein, Richard J B Dobson, David A Collier, Michael J O'Neill, Angela K Hodges, Stephen J Newhouse
Rare heterozygous coding variants in the triggering receptor expressed in myeloid cells 2 (TREM2) gene, conferring increased risk of developing late-onset Alzheimer's disease, have been identified. We examined the transcriptional consequences of the loss of Trem2 in mouse brain to better understand its role in disease using differential expression and coexpression network analysis of Trem2 knockout and wild-type mice. We generated RNA-Seq data from cortex and hippocampus sampled at 4 and 8 months. Using brain cell-type markers and ontology enrichment, we found subnetworks with cell type and/or functional identity...
May 17, 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29902745/lymphoblast-derived-integration-free-ipsc-line-ad-trem2-3-from-a-74-year-old-alzheimer-s-disease-patient-expressing-the-trem2-p-r47h-variant
#2
Soraia Martins, Hatice Yigit, Martina Bohndorf, Nina Graffmann, Aurelian Robert Fiszl, Wasco Wruck, Kristel Sleegers, Christine Van Broeckhoven, James Adjaye
Human lymphoblast cells from a male diagnosed with Alzheimer's disease (AD) expressing the TREM2 p.R47H variant were used to generate integration-free induced pluripotent stem cells (iPSCs) by over-expressing episomal-based plasmids harbouring OCT4, SOX2, KLF4, LIN28, L-MYC and p53 shRNA. The derived iPSC line - AD-TREM2-3 was defined as pluripotent based on (i) expression of pluripotency-associated markers (ii) embryoid body-based differentiation into cell types representative of the three germ layers and (iii) the similarity between the transcriptome of the iPSC line and the human embryonic stem cell line H1 with a Pearson correlation of 0...
June 1, 2018: Stem Cell Research
https://www.readbyqxmd.com/read/29889572/triggering-receptor-expressed-on-myeloid-cells-2-trem2-a-potential-therapeutic-target-for-alzheimer-disease
#3
Yuetiva Deming, Zeran Li, Bruno A Benitez, Carlos Cruchaga
There are currently no effective therapeutics for Alzheimer disease (AD). Clinical trials targeting amyloid beta thus far have shown very little benefit and only in the earliest stages of disease. These limitations have driven research to identify alternative therapeutic targets, one of the most promising is the triggering receptor expressed on myeloid cells 2 (TREM2). Areas covered: Here, we review the literature to-date and discuss the potentials and pitfalls for targeting TREM2 as a potential therapeutic for AD...
June 11, 2018: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29887864/triggering-receptors-expressed-on-myeloid-cells-2-promotes-corneal-resistance-against-pseudomonas-aeruginosa-by-inhibiting-caspase-1-dependent-pyroptosis
#4
Wenting Qu, Yi Wang, Yongjian Wu, Yiting Liu, Kang Chen, Xi Liu, Zhengyu Zou, Xi Huang, Minhao Wu
Triggering receptors expressed on myeloid cells 2 (TREM2) is a novel cell surface receptor and functions as an immunomodulatory receptor in infectious diseases. In this study, we investigated the function and regulatory mechanism of TREM2 in Pseudomonas aeruginosa ( P. aeruginosa ) keratitis. We found that P. aeruginosa keratitis was more severe in Trem2 -/- versus wild type C57BL/6 mice as indicated by the increased clinical scores, bacterial load, and cornea pathology. The exacerbated disease progression caused by TREM2 deficiency was associated with boosted activation of caspase-1 and subsequent pyroptosis as well as increased expression of IL-1β...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29880032/genetic-variants-associated-with-alzheimer-s-disease-confer-different-cerebral-cortex-cell-type-population-structure
#5
Zeran Li, Jorge L Del-Aguila, Umber Dube, John Budde, Rita Martinez, Kathleen Black, Qingli Xiao, Nigel J Cairns, Joseph D Dougherty, Jin-Moo Lee, John C Morris, Randall J Bateman, Celeste M Karch, Carlos Cruchaga, Oscar Harari
BACKGROUND: Alzheimer's disease (AD) is characterized by neuronal loss and astrocytosis in the cerebral cortex. However, the specific effects that pathological mutations and coding variants associated with AD have on the cellular composition of the brain are often ignored. METHODS: We developed and optimized a cell-type-specific expression reference panel and employed digital deconvolution methods to determine brain cellular distribution in three independent transcriptomic studies...
June 8, 2018: Genome Medicine
https://www.readbyqxmd.com/read/29859094/the-trem2-r47h-variant-confers-loss-of-function-like-phenotypes-in-alzheimer-s-disease
#6
Paul J Cheng-Hathaway, Erin G Reed-Geaghan, Taylor R Jay, Brad T Casali, Shane M Bemiller, Shweta S Puntambekar, Victoria E von Saucken, Roxanne Y Williams, J Colleen Karlo, Miguel Moutinho, Guixiang Xu, Richard M Ransohoff, Bruce T Lamb, Gary E Landreth
BACKGROUND: The R47H variant of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) confers greatly increased risk for Alzheimer's disease (AD), reflective of a central role for myeloid cells in neurodegeneration. Understanding how this variant confers AD risk promises to provide important insights into how myeloid cells contribute to AD pathogenesis and progression. METHODS: In order to investigate this mechanism, CRISPR/Cas9 was used to generate a mouse model of AD harboring one copy of the single nucleotide polymorphism (SNP) encoding the R47H variant in murine Trem2...
June 1, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29842899/the-alzheimer-s-disease-associated-trem2-gene-is-regulated-by-p53-tumor-suppressor-protein
#7
Artur Zajkowicz, Agnieszka Gdowicz-Kłosok, Małgorzata Krześniak, Patryk Janus, Barbara Łasut, Marek Rusin
TREM2 mutations evoke neurodegenerative disorders, and recently genetic variants of this gene were correlated to increased risk of Alzheimer's disease. The signaling cascade originating from the TREM2 membrane receptor includes its binding partner TYROBP, BLNK adapter protein, and SYK kinase, which can be activated by p53. Moreover, in silico identification of a putative p53 response element (RE) at the TREM2 promoter led us to hypothesize that TREM2 and other pathway elements may be regulated in p53-dependent manner...
May 26, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29794134/molecular-basis-for-the-loss-of-function-effects-of-the-alzheimer-s-disease-associated-r47h-variant-of-the-immune-receptor-trem2
#8
Athena Sudom, Santosh Talreja, Jean Danao, Eric Bragg, Rob Kegel, Xiaoshan Min, Nikolai Sharkov, Edoardo Marcora, Steve Thibault, Jodi Bradley, Steve Wood, Ai-Ching Lim, Hang Chen, Songli Wang, Ian N Foltz, Shilpa Sambashivan, Zhulun Wang
Triggering receptor expressed on myeloid cells-2 (TREM2) is an immune receptor expressed on the surface of microglia, macrophages, dendritic cells, and osteoclasts. The R47H TREM2 variant is a significant risk factor for late-onset Alzheimer's disease (AD), and the molecular basis of R47H TREM2 loss-of-function is an emerging area of TREM2 biology. Here, we report three high-resolution structures of the extracellular ligand-binding domains (ECD) of R47H TREM2, apo wild-type (WT), and phosphatidylserine (PS)-bound WT TREM2 at 1...
May 24, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29775591/disease-associated-microglia-a-universal-immune-sensor-of-neurodegeneration
#9
REVIEW
Aleksandra Deczkowska, Hadas Keren-Shaul, Assaf Weiner, Marco Colonna, Michal Schwartz, Ido Amit
A major challenge in the field of neurodegenerative diseases and brain aging is to identify the body's intrinsic mechanism that could sense the central nervous system (CNS) damage early and protect the brain from neurodegeneration. Accumulating evidence suggests that disease-associated microglia (DAM), a recently identified subset of CNS resident macrophages found at sites of neurodegeneration, might play such a protective role. Here, we propose that microglia are endowed with a dedicated sensory mechanism, which includes the Trem2 signaling pathway, to detect damage within the CNS in the form of neurodegeneration-associated molecular patterns (NAMPs)...
May 17, 2018: Cell
https://www.readbyqxmd.com/read/29773173/gene-expression-in-adverse-reaction-to-metal-debris-around-metal-on-metal-arthroplasty-an-rna-seq-based-study
#10
Antti Pemmari, Tiina Leppänen, Erja-Leena Paukkeri, Antti Eskelinen, Teemu Moilanen, Eeva Moilanen
Joint replacement surgery is a standard treatment of advanced osteoarthritis (OA). Since 2000, cobalt-chromium (CoCr) metal-on-metal (MoM) implants were widely used in hip arthroplasties. Some patients developed "adverse reaction to metal debris" (ARMD) around the prosthesis, resulting in a need for revision surgery. In the present study, we addressed the pathogenesis of ARMD by genome-wide expression analysis. Pseudosynovial ARMD tissue was obtained from revision surgery of Articular Surface Replacement (ASR, DePuy, Warsaw, IN, USA) hip arthroplasties...
July 2018: Journal of Trace Elements in Medicine and Biology
https://www.readbyqxmd.com/read/29768169/tremendous-2-be-social
#11
Narghes Calcagno, Caroline Baufeld, Charlotte Madore, Oleg Butovsky
TREM2 is known for its role in microglial phagocytosis and in neurodegenerative diseases. In this issue of Immunity, Filipello et al. (2018) show that microglial TREM2 is required for synaptic pruning in early development. TREM2-deficient mice show altered social behavior in adulthood, linking TREM2 to neurodevelopmental disease.
May 15, 2018: Immunity
https://www.readbyqxmd.com/read/29752066/the-microglial-innate-immune-receptor-trem2-is-required-for-synapse-elimination-and-normal-brain-connectivity
#12
Fabia Filipello, Raffaella Morini, Irene Corradini, Valerio Zerbi, Alice Canzi, Bernadeta Michalski, Marco Erreni, Marija Markicevic, Chiara Starvaggi-Cucuzza, Karel Otero, Laura Piccio, Francesca Cignarella, Fabio Perrucci, Matteo Tamborini, Marco Genua, Lawrence Rajendran, Elisabetta Menna, Stefania Vetrano, Margaret Fahnestock, Rosa Chiara Paolicelli, Michela Matteoli
The triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial innate immune receptor associated with a lethal form of early, progressive dementia, Nasu-Hakola disease, and with an increased risk of Alzheimer's disease. Microglial defects in phagocytosis of toxic aggregates or apoptotic membranes were proposed to be at the origin of the pathological processes in the presence of Trem2 inactivating mutations. Here, we show that TREM2 is essential for microglia-mediated synaptic refinement during the early stages of brain development...
May 3, 2018: Immunity
https://www.readbyqxmd.com/read/29750252/whole-exome-sequencing-of-an-exceptional-longevity-cohort
#13
Haakon B Nygaard, E Zeynep Erson-Omay, Xiujuan Wu, Brianne A Kent, Cecily Q Bernales, Daniel M Evans, Matthew J Farrer, Carles Vilariño-Güell, Stephen M Strittmatter
Centenarians represent a unique cohort to study the genetic basis for longevity and factors determining the risk of neurodegenerative disorders, including Alzheimer's disease (AD). The estimated genetic contribution to longevity is highest in centenarians and supercententenarians, but few genetic variants have been shown to clearly impact this phenotype. While the genetic risk for AD and other dementias is now well understood, the frequency of known dementia risk variants in centenarians is not fully characterized...
May 10, 2018: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
https://www.readbyqxmd.com/read/29748150/targeted-exome-sequencing-reveals-homozygous-trem2-r47c-mutation-presenting-with-behavioral-variant-frontotemporal-dementia-without-bone-involvement
#14
Adeline Sl Ng, Yi Jayne Tan, Zhao Yi, Moses Tandiono, Elaine Chew, Jacqueline Dominguez, Mabel Macas, Ebonne Ng, Shahul Hameed, Simon Ting, Eng King Tan, Jia Nee Foo, Nagaendran Kandiah
To identify genes associated with frontotemporal dementia (FTD) in South-East Asia, targeted exome sequencing and C9orf72 genotyping was performed in 198 subjects (52 patients with FTD and 146 healthy controls) who were screened for mutations in 12 FTD-associated genes. We detected a homozygous TREM2 R47C mutation in a patient with behavioral variant FTD without bone cysts or bone-associated phenotype. Two novel nonsense GRN mutations in 3 FTD patients from the Philippines were detected, but no known pathogenic mutations in other FTD-associated genes were found...
April 16, 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29740051/the-polymorphism-rs6918289-located-in-the-downstream-region-of-the-trem2-gene-is-associated-with-tnf-%C3%AE-levels-and-imt-f
#15
Vesna Gorenjak, Alex-Ander Aldasoro Arguinano, Sébastien Dadé, Maria G Stathopoulou, Dwaine R Vance, Christine Masson, Sophie Visvikis-Siest
Triggering receptor expressed on myeloid cells 2 (TREM2) is known for its anti-inflammatory properties during the immune response, and influences negatively on TNF-α expression levels. Genetic epidemiology studies have identified polymorphisms located in the TREM2 gene associated with neurodegenerative and chronic inflammatory diseases. TREM2 levels have been observed to affect plasma levels of TNF-α and plaque stability in symptomatic and asymptomatic patients with carotid stenosis. In this study, we investigated polymorphisms located in the TREM2 gene region and association with TNF-α levels and the intima media thickness of the femoral artery...
May 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29729150/cd200-cx3cl1-and-trem2-mediated-neuron-microglia-interactions-and-their-involvements-in-alzheimer-s-disease
#16
Lihang Zhang, Juan Xu, Jinchao Gao, Yuncheng Wu, Ming Yin, Wenjuan Zhao
Neurons and microglia are two major components in the central nervous system (CNS). The interactions between them play important roles in maintaining homeostasis of the brain. In recent years, substantial studies have focused on the interactions between neurons and microglia, revealing that microglia become reactive when the interactions are pathophysiologically interfered, usually accompanying neuronal injury, which is a common feature for Alzheimer's disease (AD). Many molecules and factors participate in these physiological and pathological processes, either in a contact-dependent or a contact-independent manner...
May 5, 2018: Reviews in the Neurosciences
https://www.readbyqxmd.com/read/29723869/genetic-analysis-of-trem2-variants-in-tunisian-patients-with-alzheimer-s-disease
#17
Zied Landoulsi, Mouna Ben Djebara, Imen Kacem, Youssef Sidhom, Rym Kefi, Sonia Abdelhak, Amina Gargouri-Berrechid, Riadh Gouider
OBJECTIVE: Rare variants in TREM2 gene have been reported to significantly increase risk of Alzheimer's disease in Caucasian populations. Hitherto, this association was not studied in North African populations. In this work, we aimed to study the association between TREM2 exon2 variants and the risk of late-onset Alzheimer's disease (LOAD) in a Tunisian population. SUBJECTS AND METHODS: We sequenced exon2 of TREM2 in a Tunisian cohort of 172 LOAD patients and 158 control subjects...
May 3, 2018: Medical Principles and Practice: International Journal of the Kuwait University, Health Science Centre
https://www.readbyqxmd.com/read/29720600/small-nuclear-rna-mediated-modulation-of-splicing-reveals-a-therapeutic-strategy-for-a-trem2-mutation-and-its-post-transcriptional-regulation
#18
Motoaki Yanaizu, Kenji Sakai, Youhei Tosaki, Yoshihiro Kino, Jun-Ichi Satoh
Loss-of-function mutations in TREM2 cause Nasu-Hakola disease (NHD), a rare genetic disease characterized by early-onset dementia with leukoencephalopathy and bone cysts. An NHD-associated mutation, c.482 + 2 T > C, disrupts the splice donor site of intron 3 and causes aberrant skipping of exon 3, resulting in the loss of full-length TREM2 protein. Here, we examined the efficacy of artificial U1 and U7 small nuclear RNAs (snRNAs) designed to enhance exon 3 inclusion. Using mutant TREM2 minigenes, we found that some modified U1, but not U7, snRNAs enhanced exon 3 inclusion and restored TREM2 protein expression...
May 2, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29705945/could-alzheimer-s-disease-originate-in-the-periphery-and-if-so-how-so
#19
REVIEW
Gerwyn Morris, Michael Berk, Michael Maes, Basant K Puri
The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD...
April 29, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29689568/upregulation-of-trem2-ameliorates-neuroinflammatory-responses-and-improves-cognitive-deficits-triggered-by-surgical-trauma-in-appswe-ps1de9-mice
#20
Yanhua Jiang, Zhe Li, Hong Ma, Xuezhao Cao, Fang Liu, Ayong Tian, Xijia Sun, Xiaoqian Li, Jun Wang
BACKGROUND/AIMS: TREM2 plays a crucial role in modulating microglial function through interaction with DAP12, the adapter for TREM2. Emerging evidence has demonstrated that TREM2 could suppress neuroinflammatory responses by repression of microglia-mediated cytokine production. This study investigated the potential role of TREM2 in surgery-induced cognitive deficits and neuroinflammatory responses in wild-type (WT) and APPswe/PS1dE9 mice. METHODS: Adult APPswe/PS1dE9 transgenic male mice (a classic transgenic model of Alzheimer's disease, 3 months old) and their age-matched WT mice received intracerebral lentiviral particles encoding the mouse TREM2 gene and then were subjected to partial hepatectomy at 1 month after the lentiviral particle injection...
April 18, 2018: Cellular Physiology and Biochemistry
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