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TREM2 microglia

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https://www.readbyqxmd.com/read/28628896/cholinergic-neuron-gene-expression-differences-captured-by-translational-profiling-in-a-mouse-model-of-alzheimer-s-disease
#1
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...
May 25, 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
#2
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
#3
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
#4
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...
June 7, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28592261/trem2-protects-against-cerebral-ischemia-reperfusion-injury
#5
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
https://www.readbyqxmd.com/read/28588439/dna-methylation-changes-in-intron-1-of-triggering-receptor-expressed-on-myeloid-cell-2-in-japanese-schizophrenia-subjects
#6
Yuta Yoshino, Yuki Ozaki, Kiyohiro Yamazaki, Tomoko Sao, Yoko Mori, Shinichiro Ochi, Jun-Ichi Iga, Shu-Ichi Ueno
A hypothesis for schizophrenia (SCZ) called the "microglia hypothesis" has been suggested. In SCZ, expression of triggering receptor expressed on myeloid cell 2 (TREM2) mRNA is higher in leukocytes than in healthy individuals. Here, the methylation rates of four CpG sites in TREM2 intron 1 that may bind important transcription factors and the correlation between the methylation rate and mRNA expression were determined. We compared the methylation rates in SCZ patients and age-matched controls (n = 50 each)...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28567000/exosomes-from-nsc-34-cells-transfected-with-hsod1-g93a-are-enriched-in-mir-124-and-drive-alterations-in-microglia-phenotype
#7
Sara Pinto, Carolina Cunha, Marta Barbosa, Ana R Vaz, Dora Brites
Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder affecting motor neurons (MNs). Evidences indicate that ALS is a non-cell autonomous disease in which glial cells participate in both disease onset and progression. Exosomal transfer of mutant copper-zinc superoxide dismutase 1 (mSOD1) from cell-to-cell was suggested to contribute to disease dissemination. Data from our group and others showed that exosomes from activated cells contain inflammatory-related microRNAs (inflamma-miRNAs) that recapitulate the donor cell...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28559417/the-ftd-like-syndrome-causing-trem2-t66m-mutation-impairs-microglia-function-brain-perfusion-and-glucose-metabolism
#8
Gernot Kleinberger, Matthias Brendel, Eva Mracsko, Benedikt Wefers, Linda Groeneweg, Xianyuan Xiang, Carola Focke, Maximilian Deußing, Marc Suárez-Calvet, Fargol Mazaheri, Samira Parhizkar, Nadine Pettkus, Wolfgang Wurst, Regina Feederle, Peter Bartenstein, Thomas Mueggler, Thomas Arzberger, Irene Knuesel, Axel Rominger, Christian Haass
Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD). Homozygous TREM2 missense mutations, such as p.T66M, lead to the FTD-like syndrome, but how they cause pathology is unknown. Using CRISPR/Cas9 genome editing, we generated a knock-in mouse model for the disease-associated Trem2 p.T66M mutation. Consistent with a loss-of-function mutation, we observe an intracellular accumulation of immature mutant Trem2 and reduced generation of soluble Trem2 similar to patients with the homozygous p...
May 30, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28549481/late-onset-alzheimer-s-disease-genetics-implicates-microglial-pathways-in-disease-risk
#9
REVIEW
Anastasia G Efthymiou, Alison M Goate
Alzheimer's disease (AD) is a highly heritable complex disease with no current effective prevention or treatment. The majority of drugs developed for AD focus on the amyloid cascade hypothesis, which implicates Aß plaques as a causal factor in the disease. However, it is possible that other underexplored disease-associated pathways may be more fruitful targets for drug development. Findings from gene network analyses implicate immune networks as being enriched in AD; many of the genes in these networks fall within genomic regions that contain common and rare variants that are associated with increased risk of developing AD...
May 26, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28490631/a-split-luciferase-complementation-real-time-reporting-assay-enables-monitoring-of-the-disease-associated-transmembrane-protein-trem2-in-live-cells
#10
Megan M Varnum, Kevin A Clayton, Asuka Yoshii-Kitahara, Grant Yonemoto, Lacin Koro, Seiko Ikezu, Tsuneya Ikezu
Triggering receptor expressed on myeloid cells 2 (TREM2) is a single transmembrane molecule uniquely expressed in microglia. TREM2 mutations are genetically linked to Nasu-Hakola disease and associated with multiple neurodegenerative disorders, including Alzheimer's disease (AD). TREM2 may regulate microglial inflammation and phagocytosis through coupling to the adaptor protein, TYRO protein tyrosine kinase binding protein (TYROBP). However, there is no functional system for monitoring this protein-protein interaction...
May 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28483841/trem2-deficiency-impairs-chemotaxis-and-microglial-responses-to-neuronal-injury
#11
Fargol Mazaheri, Nicolas Snaidero, Gernot Kleinberger, Charlotte Madore, Anna Daria, Georg Werner, Susanne Krasemann, Anja Capell, Dietrich Trümbach, Wolfgang Wurst, Bettina Brunner, Sebastian Bultmann, Sabina Tahirovic, Martin Kerschensteiner, Thomas Misgeld, Oleg Butovsky, Christian Haass
Sequence variations in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to an increased risk for neurodegenerative disorders such as Alzheimer's disease and frontotemporal lobar degeneration. In the brain, TREM2 is predominantly expressed in microglia. Several disease-associated TREM2 variants result in a loss of function by reducing microglial phagocytosis, impairing lipid sensing, preventing binding of lipoproteins and affecting shielding of amyloid plaques. We here investigate the consequences of TREM2 loss of function on the microglia transcriptome...
May 8, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28442216/trem2-microglia-and-neurodegenerative-diseases
#12
REVIEW
Felix L Yeh, David V Hansen, Morgan Sheng
Alzheimer's disease (AD) is the most common form of dementia and the 6th leading cause of death in the US. The neuropathological hallmarks of the disease are extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated tau aggregates. Genetic variants of TREM2 (triggering receptor expressed on myeloid cells 2), a cell-surface receptor expressed selectively in myeloid cells, greatly increase the risk of AD, implicating microglia and the innate immune system as pivotal factors in AD pathogenesis...
April 22, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28434692/immune-hyperreactivity-of-a%C3%AE-plaque-associated-microglia-in-alzheimer-s-disease
#13
Zhuoran Yin, Divya Raj, Nasrin Saiepour, Debby Van Dam, Nieske Brouwer, Inge R Holtman, Bart J L Eggen, Thomas Möller, Joseph A Tamm, Aicha Abdourahman, Elly M Hol, Willem Kamphuis, Thomas A Bayer, Peter P De Deyn, Erik Boddeke
Alzheimer's disease (AD) is strongly associated with microglia-induced neuroinflammation. Particularly, Aβ plaque-associated microglia take on an "activated" morphology. However, the function and phenotype of these Aβ plaque-associated microglia are not well understood. We show hyperreactivity of Aβ plaque-associated microglia upon systemic inflammation in transgenic AD mouse models (i.e., 5XFAD and APP23). Gene expression profiling of Aβ plaque-associated microglia (major histocompatibility complex II(+) microglia) isolated from 5XFAD mice revealed a proinflammatory phenotype...
March 27, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28376694/identification-of-a-rare-coding-variant-in-trem2-in-a-chinese-individual-with-alzheimer-s-disease
#14
Luke W Bonham, Daniel W Sirkis, Jia Fan, Renan E Aparicio, Marian Tse, Eliana Marisa Ramos, Qing Wang, Giovanni Coppola, Howard J Rosen, Bruce L Miller, Jennifer S Yokoyama
Rare variation in the TREM2 gene is associated with a broad spectrum of neurodegenerative disorders including Alzheimer's disease (AD). TREM2 encodes a receptor expressed in microglia which is thought to influence neurodegeneration by sensing damage signals and regulating neuroinflammation. Many of the variants reported to be associated with AD, including the rare R47H variant, were discovered in populations of European ancestry and have not replicated in diverse populations from other genetic backgrounds. We utilized a cohort of elderly Chinese individuals diagnosed as cognitively normal, or with mild cognitive impairment or AD to identify a rare variant, A192T, present in a single patient diagnosed with AD...
February 2017: Neurocase
https://www.readbyqxmd.com/read/28365005/neocortical-and-hippocampal-trem2-protein-levels-during-the-progression-of-alzheimer-s-disease
#15
Sylvia E Perez, Muhammad Nadeem, Bin He, Jennifer C Miguel, Michael H Malek-Ahmadi, Kewei Chen, Elliott J Mufson
Heterozygous triggering receptor expressed on myeloid cells (TREM2) mutations are an Alzheimer's disease (AD) risk factor. Nonmutated TREM2 dysregulation occurs in AD brain. Whether TREM2 is altered in prodromal AD remains unknown. Western blotting was used to determine levels of TREM2 (∼25 kDa) and Iba1 in the frontal cortex and TREM2 in the hippocampus from people who died with an ante-mortem clinical diagnosis of non- and mild-cognitive impairment, mild/moderate AD, and severe AD (sAD). Immunohistochemistry defined the relationship between amyloid and Iba1 profiles...
June 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28357182/expression-of-gpr17-a-regulator-of-oligodendrocyte-differentiation-and-maturation-in-nasu-hakola-disease-brains
#16
Jun-Ichi Satoh, Yoshihiro Kino, Motoaki Yanaizu, Youhei Tosaki, Kenji Sakai, Tusyoshi Ishida, Yuko Saito
The G protein-coupled receptor 17 (GPR17), a Gi-coupled GPCR, acts as an intrinsic timer of oligodendrocyte differentiation and myelination. The expression of GPR17 is upregulated during differentiation of oligodendrocyte precursor cells (OPCs) into premyelinating oligodendrocytes (preoligodendrocytes), whereas it is markedly downregulated during terminal maturation of myelinating oligodendrocytes. Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2...
February 2017: Intractable & Rare Diseases Research
https://www.readbyqxmd.com/read/28303091/divergent-neuroinflammatory-regulation-of-microglial-trem-expression-and-involvement-of-nf-%C3%AE%C2%BAb
#17
Rosie Owens, Kathleen Grabert, Claire L Davies, Alessio Alfieri, Jack P Antel, Luke M Healy, Barry W McColl
The triggering receptor expressed on myeloid cells (TREM) family of proteins are cell surface receptors with important roles in regulation of myeloid cell inflammatory activity. In the central nervous system, TREM2 is implicated in further roles in microglial homeostasis, neuroinflammation and neurodegeneration. Different TREM receptors appear to have contrasting roles in controlling myeloid immune activity therefore the relative and co-ordinated regulation of their expression is important to understand but is currently poorly understood...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28302159/a-data-driven-approach-links-microglia-to-pathology-and-prognosis-in-amyotrophic-lateral-sclerosis
#18
Johnathan Cooper-Knock, Claire Green, Gabriel Altschuler, Wenbin Wei, Joanna J Bury, Paul R Heath, Matthew Wyles, Catherine Gelsthorpe, J Robin Highley, Alejandro Lorente-Pons, Tim Beck, Kathryn Doyle, Karel Otero, Bryan Traynor, Janine Kirby, Pamela J Shaw, Winston Hide
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that lacks a predictive and broadly applicable biomarker. Continued focus on mutation-specific upstream mechanisms has yet to predict disease progression in the clinic. Utilising cellular pathology common to the majority of ALS patients, we implemented an objective transcriptome-driven approach to develop noninvasive prognostic biomarkers for disease progression. Genes expressed in laser captured motor neurons in direct correlation (Spearman rank correlation, p < 0...
March 16, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28209725/soluble-trem2-induces-inflammatory-responses-and-enhances-microglial-survival
#19
Li Zhong, Xiao-Fen Chen, Tingting Wang, Zhe Wang, Chunyan Liao, Zongqi Wang, Ruizhi Huang, Daxin Wang, Xinxiu Li, Linbei Wu, Lin Jia, Honghua Zheng, Meghan Painter, Yuka Atagi, Chia-Chen Liu, Yun-Wu Zhang, John D Fryer, Huaxi Xu, Guojun Bu
Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed in microglia in the brain. A soluble form of TREM2 (sTREM2) derived from proteolytic cleavage of the cell surface receptor is increased in the preclinical stages of AD and positively correlates with the amounts of total and phosphorylated tau in the cerebrospinal fluid. However, the physiological and pathological functions of sTREM2 remain unknown. Here, we show that sTREM2 promotes microglial survival in a PI3K/Akt-dependent manner and stimulates the production of inflammatory cytokines depending on NF-κB...
March 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28197095/increase-of-trem2-during-aging-of-an-alzheimer-s-disease-mouse-model-is-paralleled-by-microglial-activation-and-amyloidosis
#20
Matthias Brendel, Gernot Kleinberger, Federico Probst, Anna Jaworska, Felix Overhoff, Tanja Blume, Nathalie L Albert, Janette Carlsen, Simon Lindner, Franz Josef Gildehaus, Laurence Ozmen, Marc Suárez-Calvet, Peter Bartenstein, Karlheinz Baumann, Michael Ewers, Jochen Herms, Christian Haass, Axel Rominger
Heterozygous missense mutations in the triggering receptor expressed on myeloid cells 2 (TREM2) have been reported to significantly increase the risk of developing Alzheimer's disease (AD). Since TREM2 is specifically expressed by microglia in the brain, we hypothesized that soluble TREM2 (sTREM2) levels may increase together with in vivo biomarkers of microglial activity and amyloidosis in an AD mouse model as assessed by small animal positron-emission-tomography (μPET). In this cross-sectional study, we examined a strong amyloid mouse model (PS2APP) of four age groups by μPET with [(18)F]-GE180 (glial activation) and [(18)F]-florbetaben (amyloidosis), followed by measurement of sTREM2 levels and amyloid levels in the brain...
2017: Frontiers in Aging Neuroscience
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