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TREM2 microglia

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https://www.readbyqxmd.com/read/27904823/expression-of-gp91phox-and-p22phox-catalytic-subunits-of-nadph-oxidase-on-microglia-in-nasu-hakola-disease-brains
#1
Jun-Ichi Satoh, Yoshihiro Kino, Motoaki Yanaizu, Youhei Tosaki, Kenji Sakai, Tusyoshi Ishida, Yuko Saito
The superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex of phagocytes (phox) plays a key role in production of reactive oxygen species (ROS) by microglia. The catalytic subunits of the NADPH oxidase are composed of p22phox and gp91phox. Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2. Pathologically, the brains of NHD patients exhibit extensive demyelination designated leukoencephalopathy, astrogliosis, accumulation of axonal spheroids, and remarkable activation of microglia predominantly in the white matter of frontal and temporal lobes...
November 2016: Intractable & Rare Diseases Research
https://www.readbyqxmd.com/read/27904822/targeted-sequencing-approach-to-identify-genetic-mutations-in-nasu-hakola-disease
#2
Jun-Ichi Satoh, Motoaki Yanaizu, Youhei Tosaki, Kenji Sakai, Yoshihiro Kino
Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by sclerosing leukoencephalopathy and multifocal bone cysts, caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2. TREM2 and DAP12 constitute a receptor/adaptor signaling complex expressed exclusively on osteoclasts, dendritic cells, macrophages, and microglia. Premortem molecular diagnosis of NHD requires genetic analysis of both TYROBP and TREM2, in which 20 distinct NHD-causing mutations have been reported. Due to genetic heterogeneity, it is often difficult to identify the exact mutation responsible for NHD...
November 2016: Intractable & Rare Diseases Research
https://www.readbyqxmd.com/read/27859676/microglia-and-brain-macrophages-an-update
#3
REVIEW
Atsushi Sasaki
Current immunohistochemical techniques have made the identification of microglia possible in routinely processed tissue sections from human brains. Previous studies have indicated that almost no neurological diseases exist without microglial activation. Activated microglia often secrete inflammatory cytokines in various diseases, including Alzheimer's disease, but microglial activation is not always associated with inflammation. The equation microglial activation means "neuroinflammation" is absurd and misleading...
November 18, 2016: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/27798193/trem2-dap12-signal-elicits-proinflammatory-response-in-microglia-and-exacerbates-neuropathic-pain
#4
Masaaki Kobayashi, Hiroyuki Konishi, Akira Sayo, Toshiyuki Takai, Hiroshi Kiyama
: Neuropathic pain afflicts millions of people, and the development of an effective treatment for this intractable pain is an urgent issue. Recent evidence has implicated microglia in neuropathic pain. The present study showed that the DNAX-activating protein of 12 kDa (DAP12) and its associated "triggering receptor expressed on myeloid cells 2" (TREM2) were predominantly expressed by microglia in the dorsal horn after spinal nerve injury, revealing a role for TREM2/DAP12 signaling in neuropathic pain...
October 26, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27717139/vps35-dependent-recycling-of-trem2-regulates-microglial-function
#5
Jie Yin, Xiaocui Liu, Qing He, Lujun Zhou, Zengqiang Yuan, Siqi Zhao
Triggering receptor expressed on myeloid cells 2 (Trem2), an immune-modulatory receptor, is preferentially expressed in microglia of central nervous system. Trem2 might be involved in the development of Alzheimer's disease (AD) through regulating the inflammatory responses and phagocytosis of microglia. However, the intracellular trafficking of Trem2 remains unclear. In this study, we showed that Trem2 in the plasma membrane underwent endocytosis and recycling. Trem2 is internalized in a clathrin-dependent manner and then recycled back to the plasma membrane through vacuolar protein sorting 35 (Vps35), the key component of cargo recognition core of retromer complex, but not Rab11...
September 26, 2016: Traffic
https://www.readbyqxmd.com/read/27710785/trem2-haplodeficiency-in-mice-and-humans-impairs-the-microglia-barrier-function-leading-to-decreased-amyloid-compaction-and-severe-axonal-dystrophy
#6
Peng Yuan, Carlo Condello, C Dirk Keene, Yaming Wang, Thomas D Bird, Steven M Paul, Wenjie Luo, Marco Colonna, David Baddeley, Jaime Grutzendler
No abstract text is available yet for this article.
October 5, 2016: Neuron
https://www.readbyqxmd.com/read/27589997/rare-trem2-variants-associated-with-alzheimer-s-disease-display-reduced-cell-surface-expression
#7
Daniel W Sirkis, Luke W Bonham, Renan E Aparicio, Ethan G Geier, Eliana Marisa Ramos, Qing Wang, Anna Karydas, Zachary A Miller, Bruce L Miller, Giovanni Coppola, Jennifer S Yokoyama
Rare variation in TREM2 has been associated with greater risk for Alzheimer's disease (AD). TREM2 encodes a cell surface receptor expressed on microglia and related cells, and the R47H variant associated with AD appears to affect the ability of TREM2 to bind extracellular ligands. In addition, other rare TREM2 mutations causing early-onset neurodegeneration are thought to impair cell surface expression. Using a sequence kernel association (SKAT) analysis in two independent AD cohorts, we found significant enrichment of rare TREM2 variants not previously characterized at the protein level...
September 2, 2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27520774/alzheimer-s-disease-associated-trem2-variants-exhibit-either-decreased-or-increased-ligand-dependent-activation
#8
Wilbur Song, Basavaraj Hooli, Kristina Mullin, Sheng Chih Jin, Marina Cella, Tyler K Ulland, Yaming Wang, Rudolph Tanzi, Marco Colonna
INTRODUCTION: TREM2 is a lipid-sensing activating receptor on microglia known to be important for Alzheimer's disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial. METHODS: We analyzed AD risk of TREM2 variants in the NIMH AD Genetics Initiative Study and AD Sequencing Project. We compared each variant's risk and functional impact by a reporter assay. Finally, we analyzed expression of TREM2 on human monocytes...
August 9, 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/27516385/the-human-specific-casp4-gene-product-contributes-to-alzheimer-related-synaptic-and-behavioural-deficits
#9
Yuji Kajiwara, Andrew McKenzie, Nate Dorr, Miguel A Gama Sosa, Gregory Elder, James Schmeidler, Dara L Dickstein, Ozlem Bozdagi, Bin Zhang, Joseph D Buxbaum
Recent studies have indicated that innate immune signalling molecules are involved in late-onset Alzheimer's disease (LOAD) risk. Amyloid beta (Aβ) accumulates in AD brain, and has been proposed to act as a trigger of innate immune responses. Caspase-4 is an important part of the innate immune response. We recently characterized transgenic mice carrying human CASP4, and observed that the mice manifested profound innate immune responses to lipopolysaccharide (LPS). Since these inflammatory processes are important in the aetiology of AD, we have now analysed the correlation of expression of caspase-4 in human brain with AD risk genes, and studied caspase-4 effects on AD-related phenotypes in APPswe/PS1deltaE9 (APP/PS1) mice...
August 11, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27477018/trem2-binds-to-apolipoproteins-including-apoe-and-clu-apoj-and-thereby-facilitates-uptake-of-amyloid-beta-by-microglia
#10
Felix L Yeh, Yuanyuan Wang, Irene Tom, Lino C Gonzalez, Morgan Sheng
Genetic variants of TREM2, a protein expressed selectively by microglia in the brain, are associated with Alzheimer's disease (AD). Starting from an unbiased protein microarray screen, we identified a set of lipoprotein particles (including LDL) and apolipoproteins (including CLU/APOJ and APOE) as ligands of TREM2. Binding of these ligands by TREM2 was abolished or reduced by disease-associated mutations. Overexpression of wild-type TREM2 was sufficient to enhance uptake of LDL, CLU, and APOE in heterologous cells, whereas TREM2 disease variants were impaired in this activity...
July 20, 2016: Neuron
https://www.readbyqxmd.com/read/27402340/trem2-deficiency-reduces-the-efficacy-of-immunotherapeutic-amyloid-clearance
#11
Xianyuan Xiang, Georg Werner, Bernd Bohrmann, Arthur Liesz, Fargol Mazaheri, Anja Capell, Regina Feederle, Irene Knuesel, Gernot Kleinberger, Christian Haass
Immunotherapeutic approaches are currently the most advanced treatments for Alzheimer's disease (AD). Antibodies against amyloid β-peptide (Aβ) bind to amyloid plaques and induce their clearance by microglia via Fc receptor-mediated phagocytosis. Dysfunctions of microglia may play a pivotal role in AD pathogenesis and could result in reduced efficacy of antibody-mediated Aβ clearance. Recently, heterozygous mutations in the triggering receptor expressed on myeloid cells 2 (TREM2), a microglial gene involved in phagocytosis, were genetically linked to late onset AD Loss of TREM2 reduces the ability of microglia to engulf Aβ...
September 1, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27248001/targeting-innate-immunity-for-neurodegenerative-disorders-of-the-central-nervous-system
#12
REVIEW
Katrin I Andreasson, Adam D Bachstetter, Marco Colonna, Florent Ginhoux, Clive Holmes, Bruce Lamb, Gary Landreth, Daniel C Lee, Donovan Low, Marina A Lynch, Alon Monsonego, M Kerry O'Banion, Milos Pekny, Till Puschmann, Niva Russek-Blum, Leslie A Sandusky, Maj-Linda B Selenica, Kazuyuki Takata, Jessica Teeling, Terrence Town, Linda J Van Eldik
Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance...
September 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27196974/trem2-haplodeficiency-in-mice-and-humans-impairs-the-microglia-barrier-function-leading-to-decreased-amyloid-compaction-and-severe-axonal-dystrophy
#13
Peng Yuan, Carlo Condello, C Dirk Keene, Yaming Wang, Thomas D Bird, Steven M Paul, Wenjie Luo, Marco Colonna, David Baddeley, Jaime Grutzendler
Haplodeficiency of the microglia gene TREM2 increases risk for late-onset Alzheimer's disease (AD) but the mechanisms remain uncertain. To investigate this, we used high-resolution confocal and super-resolution (STORM) microscopy in AD-like mice and human AD tissue. We found that microglia processes, rich in TREM2, tightly surround early amyloid fibrils and plaques promoting their compaction and insulation. In Trem2- or DAP12-haplodeficient mice and in humans with R47H TREM2 mutations, microglia had a markedly reduced ability to envelop amyloid deposits...
May 18, 2016: Neuron
https://www.readbyqxmd.com/read/27156507/-molecular-pathogenesis-of-nasu-hakola-disease-brain-lesions
#14
Jun-Ichi Satoh
Nasu-Hakola disease (NHD) is a rare intractable autosomal recessive disorder, characterized by pathological bone fractures and progressive dementia owing to multifocal bone cysts and leukoencephalopathy, caused by various genetic mutations of either DAP12 or TREM2. Loss-of-function of TREM2-DAP12, constituting a signaling complex on osteoclasts and microglia, plays a central role in the pathogenesis of NHD. Recently, NHD has been recognized as the disease entity designated "microgliopathy". However, at present, TREM2-specific ligands in microglia and the precise molecular mechanism underlying leukoencephalopathy remain to be investigated in order to establish an effective molecular targeted therapy for NHD...
May 2016: Brain and Nerve, Shinkei Kenkyū No Shinpo
https://www.readbyqxmd.com/read/27143430/opposing-roles-of-the-triggering-receptor-expressed-on-myeloid-cells-2-and-triggering-receptor-expressed-on-myeloid-cells-like-transcript-2-in-microglia-activation
#15
Honghua Zheng, Chia-Chen Liu, Yuka Atagi, Xiao-Fen Chen, Lin Jia, Longyu Yang, Wencan He, Xilin Zhang, Silvia S Kang, Terrone L Rosenberry, John D Fryer, Yun-Wu Zhang, Huaxi Xu, Guojun Bu
Mutations in triggering receptor expressed on myeloid cells 2 (TREM2), which has been proposed to regulate the inflammatory responses and the clearance of apoptotic neurons and/or amyloid-β, are genetically linked to increased risk for late-onset Alzheimer's disease (AD). Interestingly, a missense variant in TREM-like transcript 2 (TREML2), a structurally similar protein encoded by the same gene cluster with TREM2 on chromosome 6, has been shown to protect against AD. However, the molecular mechanisms by which TREM2 and TREML2 regulate the pathogenesis of AD, and their functional relationship, if any, remain unclear...
June 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/27130565/elevated-trem2-mrna-expression-in-leukocytes-in-schizophrenia-but-not-major-depressive-disorder
#16
Yuta Yoshino, Kentaro Kawabe, Kiyohiro Yamazaki, Shinya Watanabe, Shusuke Numata, Yoko Mori, Taku Yoshida, Junichi Iga, Tetsuro Ohmori, Shu-Ichi Ueno
The pathological mechanisms of schizophrenia (SCZ) have not been clarified, but the microglia hypothesis has recently been discussed. We previously reported that the mRNA for a protein related to activation of microglia, triggering receptor expressed on myeloid cell 2 (TREM2), is expressed higher in peripheral leukocytes in SCZ than controls. In this study, we analyzed TREM2 mRNA expression in leukocytes from both SCZ and major depressive disorder (MDD) patients. We compared 50 SCZ patients and 42 MDD patients with age-matched controls...
June 2016: Journal of Neural Transmission
https://www.readbyqxmd.com/read/27100611/targeting-microglia-for-the-treatment-of-alzheimer-s-disease
#17
REVIEW
Paul D Wes, Faten A Sayed, Frédérique Bard, Li Gan
While histological changes in microglia have long been recognized as a pathological feature of Alzheimer's disease (AD), recent genetic association studies have also strongly implicated microglia in the etiology of the disease. Coding and noncoding polymorphisms in several genes expressed in microglia-including APOE, TREM2, CD33, GRN, and IL1RAP-alter AD risk, and therefore could be considered as entry points for therapeutic intervention. Furthermore, microglia may have a substantial effect on current amyloid β (Aβ) and tau immunotherapy approaches, since they are the primary cell type in the brain to mediate Fc receptor-facilitated antibody effector function...
October 2016: Glia
https://www.readbyqxmd.com/read/27091843/trem2-mediated-early-microglial-response-limits-diffusion-and-toxicity-of-amyloid-plaques
#18
Yaming Wang, Tyler K Ulland, Jason D Ulrich, Wilbur Song, John A Tzaferis, Justin T Hole, Peng Yuan, Thomas E Mahan, Yang Shi, Susan Gilfillan, Marina Cella, Jaime Grutzendler, Ronald B DeMattos, John R Cirrito, David M Holtzman, Marco Colonna
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor that recognizes changes in the lipid microenvironment, which may occur during amyloid β (Aβ) accumulation and neuronal degeneration in Alzheimer's disease (AD). Rare TREM2 variants that affect TREM2 function lead to an increased risk of developing AD. In murine models of AD, TREM2 deficiency prevents microglial clustering around Aβ deposits. However, the origin of myeloid cells surrounding amyloid and the impact of TREM2 on Aβ accumulation are a matter of debate...
May 2, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/26984535/chronic-toxoplasma-gondii-infection-enhances-%C3%AE-amyloid-phagocytosis-and-clearance-by-recruited-monocytes
#19
Luisa Möhle, Nicole Israel, Kristin Paarmann, Markus Krohn, Sabine Pietkiewicz, Andreas Müller, Inna N Lavrik, Jeffrey S Buguliskis, Björn H Schott, Dirk Schlüter, Eckart D Gundelfinger, Dirk Montag, Ulrike Seifert, Jens Pahnke, Ildiko Rita Dunay
INTRODUCTION: Alzheimer's disease (AD) is associated with the accumulation of β-amyloid (Aβ) as senile plaques in the brain, thus leading to neurodegeneration and cognitive impairment. Plaque formation depends not merely on the amount of generated Aβ peptides, but more importantly on their effective removal. Chronic infections with neurotropic pathogens, most prominently the parasite Toxoplasma (T.) gondii, are frequent in the elderly, and it has been suggested that the resulting neuroinflammation may influence the course of AD...
2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/26976047/triggering-receptor-expressed-on-myeloid-cells-2-deficiency-alters-acute-macrophage-distribution-and-improves-recovery-after-traumatic-brain-injury
#20
Maha Saber, Olga Kokiko-Cochran, Shweta S Puntambekar, Justin D Lathia, Bruce T Lamb
Traumatic brain injury (TBI) affects 1.7 million persons annually in the United States (Centers for Disease Control and Prevention). There is increasing evidence that persons exposed to TBI have increased risk of the development of multiple neurodegenerative conditions, including Alzheimer disease (AD). TBI triggers a strong neuroinflammatory response characterized by astrogliosis, activation of microglia, and infiltration of peripheral monocytes. Recent evidence suggests that alterations in innate immunity promote neurodegeneration...
May 9, 2016: Journal of Neurotrauma
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