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TREM2 microglia

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https://www.readbyqxmd.com/read/29663649/trem2-inhibits-inflammatory-responses-in-mouse-microglia-by-suppressing-the-pi3k-nf-%C3%AE%C2%BAb-signaling
#1
Caixia Li, Bing Zhao, Caizhao Lin, Zhiping Gong, Xiaoxia An
This study aimed to investigate the effects of triggering receptor expressed on myeloid cell-2 (TREM2) on the production of pro-inflammatory mediators and cytokines induced by lipopolysaccharide (LPS) in BV2 microglia. TREM2 expression or TREM2-specific siRNA were used to induce TREM2 overexpression or silencing. The BV2 cells were pre-treated with the PI3K inhibitor of LY294002 for1 h and stimulated with LPS for 24 h. Then, the cell viability, apoptosis, phagocytosis, nitric oxide (NO), lactate dehydrogenase (LDH) and cytokine production, as well as the activation of AKT and NF-kB were determined, respectively...
April 16, 2018: Cell Biology International
https://www.readbyqxmd.com/read/29655369/trem2-regulates-innate-immunity-in-alzheimer-s-disease
#2
REVIEW
Jiang-Tao Li, Ying Zhang
Recent research has shown that the triggering receptor expressed on myeloid cells 2 (TREM2) in microglia is closely related to the pathogenesis of Alzheimer's disease (AD). The mechanism of this relationship, however, remains unclear. TREM2 is part of the TREM family of receptors, which are expressed primarily in myeloid cells, including monocytes, dendritic cells, and microglia. The TREM family members are cell surface glycoproteins with an immunoglobulin-like extracellular domain, a transmembrane region and a short cytoplasmic tail region...
April 14, 2018: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29621548/trem2-modulates-microglia-phenotypes-in-the-neuroinflammation-of-parkinson-s-disease
#3
Youwen Zhang, Shujun Feng, Kun Nie, Yan Li, Yuyuan Gao, Rong Gan, Limin Wang, Bing Li, Xuegang Sun, Lijuan Wang, Yuhu Zhang
Neuroinflammation and overactivated microglia underlies the pathogenesis of Parkinson's disease (PD). Furthermore, microglia could polarize into classic inflammatory M1 and immunosuppressive M2 phenotype. Thus, inhibiting the overactivated inflammatory M1 microglia by promoting the transformation of microglia to the protective M2 phenotype provides potential therapy for PD, but the mechanism that modulates microglia polarization remains unknown. Triggering receptor expressed on myeloid cells-2 (TREM2) is a recently identified immune receptor expressed by the microglia in the brain...
April 2, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29611543/intracellular-trafficking-of-trem2-is-regulated-by-presenilin-1
#4
Yingjun Zhao, Xiaoguang Li, Timothy Huang, Lu-Lin Jiang, Zhenqiu Tan, Muxian Zhang, Irene Han-Juo Cheng, Xin Wang, Guojun Bu, Yun-Wu Zhang, Qi Wang, Huaxi Xu
Genetic mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to a variety of neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Parkinson's disease. In the brain, TREM2 is highly expressed on the cell surface of microglia, where it can transduce signals to regulate microglial functions such as phagocytosis. To date, mechanisms underlying intracellular trafficking of TREM2 remain elusive. Mutations in the presenilin 1 (PS1) catalytic subunit of the γ-secretase complex have been associated with increased generation of the amyloidogenic Aβ (amyloid-β) 42 peptide through cleavage of the Aβ precursor amyloid precursor protein...
December 1, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29606617/functional-studies-of-missense-trem2-mutations-in-human-stem-cell-derived-microglia
#5
Philip W Brownjohn, James Smith, Ravi Solanki, Ebba Lohmann, Henry Houlden, John Hardy, Sabine Dietmann, Frederick J Livesey
The derivation of microglia from human stem cells provides systems for understanding microglial biology and enables functional studies of disease-causing mutations. We describe a robust method for the derivation of human microglia from stem cells, which are phenotypically and functionally comparable with primary microglia. We used stem cell-derived microglia to study the consequences of missense mutations in the microglial-expressed protein triggering receptor expressed on myeloid cells 2 (TREM2), which are causal for frontotemporal dementia-like syndrome and Nasu-Hakola disease...
April 10, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29601944/cellular-players-that-shape-evolving-pathology-and-neurodegeneration-following-traumatic-brain-injury
#6
REVIEW
Shweta S Puntambekar, Maha Saber, Bruce T Lamb, Olga N Kokiko-Cochran
Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide, and has emerged as a critical risk factor for multiple neurodegenerative diseases, particularly Alzheimer's disease (AD). How the inflammatory cascade resulting from mechanical stress, axonal shearing and the loss of neurons and glia following initial impact in TBI, contributes to the development of AD-like disease is unclear. Neuroinflammation, characterized by blood-brain barrier (BBB) dysfunction and activation of brain-resident microglia and astrocytes, resulting in secretion of inflammatory mediators and subsequent recruitment of peripheral immune cells has been the focus of extensive research in attempts to identify drug-targets towards improving functional outcomes post TBI...
March 27, 2018: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29599291/trem2-activating-antibodies-abrogate-the-negative-pleiotropic-effects-of-the-alzheimer-s-disease-variant-trem2-r47h-on-murine-myeloid-cell-function
#7
Qingwen Cheng, Jean Danao, Santosh Talreja, Paul Wen, Jun Yin, Ning Sun, Chi-Ming Li, Danny Chui, David Tran, Samir Koirala, Hang Chen, Ian N Foltz, Songli Wang, Shilpa Sambashivan
Triggering receptor expressed on myeloid cells 2 (TREM2) is an orphan immune receptor expressed on cells of myeloid lineage such as macrophages and microglia. The rare-variant R47H TREM2 is associated with an increased risk for Alzheimer's disease (AD), supporting the hypothesis that TREM2 loss of function may exacerbate disease progression. However, a complete knockout of the TREM2 gene in different genetic models of neurodegenerative diseases has been reported to result in both protective and deleterious effects on disease-related endpoints and myeloid cell function...
March 29, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29598827/integrated-biology-approach-reveals-molecular-and-pathological-interactions-among-alzheimer-s-a%C3%AE-42-tau-trem2-and-tyrobp-in-drosophila-models
#8
Michiko Sekiya, Minghui Wang, Naoki Fujisaki, Yasufumi Sakakibara, Xiuming Quan, Michelle E Ehrlich, Philip L De Jager, David A Bennett, Eric E Schadt, Sam Gandy, Kanae Ando, Bin Zhang, Koichi M Iijima
BACKGROUND: Cerebral amyloidosis, neuroinflammation, and tauopathy are key features of Alzheimer's disease (AD), but interactions among these features remain poorly understood. Our previous multiscale molecular network models of AD revealed TYROBP as a key driver of an immune- and microglia-specific network that was robustly associated with AD pathophysiology. Recent genetic studies of AD further identified pathogenic mutations in both TREM2 and TYROBP. METHODS: In this study, we systematically examined molecular and pathological interactions among Aβ, tau, TREM2, and TYROBP by integrating signatures from transgenic Drosophila models of AD and transcriptome-wide gene co-expression networks from two human AD cohorts...
March 29, 2018: Genome Medicine
https://www.readbyqxmd.com/read/29587871/amyloid-beta-modulates-microglial-responses-by-binding-to-the-triggering-receptor-expressed-on-myeloid-cells-2-trem2
#9
Li Zhong, Zongqi Wang, Daxin Wang, Zhe Wang, Yuka A Martens, Linbei Wu, Ying Xu, Kai Wang, Jianguo Li, Ruizhi Huang, Dan Can, Huaxi Xu, Guojun Bu, Xiao-Fen Chen
BACKGROUND: TREM2 is an innate immune receptor specifically expressed in microglia. Coding variations in TREM2 have been reported to increase the risk for Alzheimer's disease (AD) and other neurodegenerative diseases. While multiple studies support a role for TREM2 in microglial recruitment to amyloid plaques, the chemoattractant factor modulating TREM2-dependent microglial responses has not been defined. METHODS: Potential binding of oligomeric amyloid-β 1-42 (oAβ1-42 ) to TREM2 was tested by complementary approaches including solid phase binding, surface plasmon resonance and immunoprecipitation assays...
March 27, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29557178/trem2-variants-in-neurodegenerative-disorders-in-the-polish-population-homozygosity-and-compound-heterozygosity-in-ftd-patients
#10
Beata Peplonska, Mariusz Berdynski, Monika Mandecka, Anna Barczak, Magdalena Kuzma-Kozakiewicz, Maria Barcikowska, Cezary Zekanowski
Activation of the TREM2 receptor on microglia stimulates phagocytosis and decreases the microglial proinflammatory response. Mutations in exon 2 of the TREM2 gene have been reported to be associated with various neurodegenerative diseases characterized by chronic inflammation. The aim of our study was to evaluate exon 2 of TREM2 gene variants as a putative genetic risk factor for Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) in the Polish population. The results were interpreted using previously published data, especially highlighting differences in the prevalence of the variants among Caucasian subpopulations across different geographic regions...
March 20, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/29552443/alzheimer-s-disease-pathology-in-nasu-hakola-disease-brains
#11
Jun-Ichi Satoh, Yoshihiro Kino, Motoaki Yanaizu, Yuko Saito
Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of either triggering receptor expressed on myeloid cells 2 ( TREM2 ) or TYRO protein tyrosine kinase binding protein ( TYROBP ), alternatively named DNAX-activation protein 12 ( DAP12 ), both of which are expressed on microglia in the brain and form the receptor-adaptor complex that chiefly recognizes anionic lipids. TREM2 transmits the signals involved in microglial survival, proliferation, chemotaxis, and phagocytosis...
February 2018: Intractable & Rare Diseases Research
https://www.readbyqxmd.com/read/29552013/differential-phagocytic-properties-of-cd45-low-microglia-and-cd45-high-brain-mononuclear-phagocytes-activation-and-age-related-effects
#12
Srikant Rangaraju, Syed Ali Raza, Noel Xiang'An Li, Ranjita Betarbet, Eric B Dammer, Duc Duong, James J Lah, Nicholas T Seyfried, Allan I Levey
In the central nervous system (CNS), microglia are innate immune mononuclear phagocytes (CNS MPs) that can phagocytose infectious particles, apoptotic cells, neurons, and pathological protein aggregates, such as Aβ in Alzheimer's disease (AD). While CD11b+ CD45low microglia account for the majority of CNS MPs, a small population of CD11b+ CD45high CNS MPs is also recognized in AD that surround Aβ plaques. These transcriptionally and pathologically unique CD45high cells have unclear origin and undefined phagocytic characteristics...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29518357/elevated-trem2-gene-dosage-reprograms-microglia-responsivity-and-ameliorates-pathological-phenotypes-in-alzheimer-s-disease-models
#13
C Y Daniel Lee, Anthony Daggett, Xiaofeng Gu, Lu-Lin Jiang, Peter Langfelder, Xiaoguang Li, Nan Wang, Yingjun Zhao, Chang Sin Park, Yonatan Cooper, Isabella Ferando, Istvan Mody, Giovanni Coppola, Huaxi Xu, X William Yang
Variants of TREM2 are associated with Alzheimer's disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes...
March 7, 2018: Neuron
https://www.readbyqxmd.com/read/29448957/brain-region-specific-enhancement-of-remyelination-and-prevention-of-demyelination-by-the-csf1r-kinase-inhibitor-blz945
#14
Nicolau Beckmann, Elisa Giorgetti, Anna Neuhaus, Stefan Zurbruegg, Nathalie Accart, Paul Smith, Julien Perdoux, Ludovic Perrot, Mark Nash, Sandrine Desrayaud, Peter Wipfli, Wilfried Frieauff, Derya R Shimshek
Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system (CNS). While multiple effective immunomodulatory therapies for MS exist today, they lack the scope of promoting CNS repair, in particular remyelination. Microglia play a pivotal role in regulating myelination processes, and the colony-stimulating factor 1 (CSF-1) pathway is a key regulator for microglia differentiation and survival. Here, we investigated the effects of the CSF-1 receptor kinase inhibitor, BLZ945, on central myelination processes in the 5-week murine cuprizone model by non-invasive and longitudinal magnetic resonance imaging (MRI) and histology...
February 15, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29411406/apoe-%C3%AE%C2%B54-is-also-required-in-trem2-r47h-variant-carriers-for-alzheimer-s-disease-to-develop
#15
Christina E Murray, Andrew King, Claire Troakes, Angela Hodges, Tammaryn Lashley
In late-onset Alzheimer's disease (AD), the ε4 allele of the apolipoprotein E gene (APOE) is the major known genetic risk factor [1]. In 2013 two research groups reported the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), is associated with AD by almost as much as APOE ε4 [2,3]. A loss-of-function R47H mutation in TREM2 is also one of the strongest single allele genetic risk factors for AD [2,3], providing a link between microglia dysfunction and AD pathogenesis. TREM2 encodes a single-pass type I membrane protein that forms a receptor-signaling complex with the TYRO protein tyrosine kinase-binding protein (TYROBP) triggering immune responses in certain macrophages and dendritic cells...
February 7, 2018: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/29407460/trem2-overexpression-attenuates-neuroinflammation-and-protects-dopaminergic-neurons-in-experimental-models-of-parkinson-s-disease
#16
Manru Ren, Ying Guo, Xinbing Wei, Shaoqi Yan, Yue Qin, Xiumei Zhang, Fan Jiang, Haiyan Lou
Triggering receptor expressed on myeloid cells-2 (TREM2) was a newly identified receptor expressed on microglia. Several observations support the hypothesis that TREM2 variation may confer susceptibility to Parkinson's disease (PD). Therefore, in this paper, we explored the role of TREM2 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Our results revealed that overexpression of TREM2 remarkably reduced MPTP-induced neuropathology including the dopaminergic neurodegeneration and neuroinflammation in vivo...
January 27, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29362997/trem2-ameliorates-neuronal-tau-pathology-through-suppression-of-microglial-inflammatory-response
#17
Teng Jiang, Ying-Dong Zhang, Qing Gao, Zhou Ou, Peng-Yu Gong, Jian-Quan Shi, Liang Wu, Jun-Shan Zhou
As a recently identified susceptibility gene for Alzheimer's disease (AD), triggering receptor expressed on myeloid cells 2 (TREM2) encodes an immune receptor that is uniquely expressed on microglia, functioning as a modulator of microglial functions including phagocytosis and inflammatory response. Several lines of evidence suggest that TREM2 is upregulated and positively correlates with tau pathology in the brains of AD patients. Meanwhile, our recent study showed that knockdown of TREM2 markedly exacerbated neuronal tau hyperphosphorylation in the brains of P301S-tau transgenic mice, implying that TREM2 might exert a protective role against tau pathology under AD context...
January 23, 2018: Inflammation
https://www.readbyqxmd.com/read/29361745/microglia-and-aging-the-role-of-the-trem2-dap12-and-cx3cl1-cx3cr1-axes
#18
REVIEW
Carmen Mecca, Ileana Giambanco, Rosario Donato, Cataldo Arcuri
Depending on the species, microglial cells represent 5-20% of glial cells in the adult brain. As the innate immune effector of the brain, microglia are involved in several functions: regulation of inflammation, synaptic connectivity, programmed cell death, wiring and circuitry formation, phagocytosis of cell debris, and synaptic pruning and sculpting of postnatal neural circuits. Moreover, microglia contribute to some neurodevelopmental disorders such as Nasu-Hakola disease (NHD), and to aged-associated neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and others...
January 22, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29321225/humanized-trem2-mice-reveal-microglia-intrinsic-and-extrinsic-effects-of-r47h-polymorphism
#19
Wilbur M Song, Satoru Joshita, Yingyue Zhou, Tyler K Ulland, Susan Gilfillan, Marco Colonna
Alzheimer's disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-β plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown...
March 5, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29278889/erythromyeloid-derived-trem2-a-major-determinant-of-alzheimer-s-disease-pathology-in-down-syndrome
#20
Ruma Raha-Chowdhury, James W Henderson, Animesh Alexander Raha, Simon R W Stott, Romina Vuono, Simona Foscarin, Liam Wilson, Tiina Annus, Robert Fincham, Kieren Allinson, Vinod Devalia, Robert P Friedland, Anthony Holland, Shahid H Zaman
BACKGROUND: Down syndrome (DS; trisomy 21) individuals have a spectrum of hematopoietic and neuronal dysfunctions and by the time they reach the age of 40 years, almost all develop Alzheimer's disease (AD) neuropathology which includes senile plaques and neurofibrillary tangles. Inflammation and innate immunity are key players in AD and DS. Triggering receptor expressed in myeloid cells-2 (TREM2) variants have been identified as risk factors for AD and other neurodegenerative diseases...
2018: Journal of Alzheimer's Disease: JAD
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