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TREM2 microglia

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 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 Vps35, the key component of cargo recognition core of retromer complex, but not Rab11...
September 26, 2016: Traffic
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
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...
2016: Acta Neuropathologica Communications
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
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
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
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...
2016: EMBO Molecular Medicine
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
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
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
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
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
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
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
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
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
Marc Suárez-Calvet, Gernot Kleinberger, Miguel Ángel Araque Caballero, Matthias Brendel, Axel Rominger, Daniel Alcolea, Juan Fortea, Alberto Lleó, Rafael Blesa, Juan Domingo Gispert, Raquel Sánchez-Valle, Anna Antonell, Lorena Rami, José L Molinuevo, Frederic Brosseron, Andreas Traschütz, Michael T Heneka, Hanne Struyfs, Sebastiaan Engelborghs, Kristel Sleegers, Christine Van Broeckhoven, Henrik Zetterberg, Bengt Nellgård, Kaj Blennow, Alexander Crispin, Michael Ewers, Christian Haass
TREM2 is an innate immune receptor expressed on the surface of microglia. Loss-of-function mutations of TREM2 are associated with increased risk of Alzheimer's disease (AD). TREM2 is a type-1 protein with an ectodomain that is proteolytically cleaved and released into the extracellular space as a soluble variant (sTREM2), which can be measured in the cerebrospinal fluid (CSF). In this cross-sectional multicenter study, we investigated whether CSF levels of sTREM2 are changed during the clinical course of AD, and in cognitively normal individuals with suspected non-AD pathology (SNAP)...
2016: EMBO Molecular Medicine
Marco Colonna, Yaming Wang
Genome-wide association studies have identified rare variants of the gene that encodes triggering receptor expressed on myeloid cells 2 (TREM2) - an immune receptor that is found in brain microglia - as risk factors for non-familial Alzheimer disease (AD). Furthermore, animal studies have indicated that microglia have an important role in the brain response to amyloid-β (Aβ) plaques and that TREM2 variants may have an impact on such a function. We discuss how TREM2 may control the microglial response to Aβ and its impact on microglial senescence, as well as the interaction of TREM2 with other molecules that are encoded by gene variants associated with AD and the hypothetical consequences of the cleavage of TREM2 from the cell surface...
April 2016: Nature Reviews. Neuroscience
Leah C Graham, Jeffrey M Harder, Ileana Soto, Wilhelmine N de Vries, Simon W M John, Gareth R Howell
Studies have assessed individual components of a western diet, but no study has assessed the long-term, cumulative effects of a western diet on aging and Alzheimer's disease (AD). Therefore, we have formulated the first western-style diet that mimics the fat, carbohydrate, protein, vitamin and mineral levels of western diets. This diet was fed to aging C57BL/6J (B6) mice to identify phenotypes that may increase susceptibility to AD, and to APP/PS1 mice, a mouse model of AD, to determine the effects of the diet in AD...
2016: Scientific Reports
Kanchan Bisht, Kaushik P Sharma, Cynthia Lecours, Maria Gabriela Sánchez, Hassan El Hajj, Giampaolo Milior, Adrián Olmos-Alonso, Diego Gómez-Nicola, Giamal Luheshi, Luc Vallières, Igor Branchi, Laura Maggi, Cristina Limatola, Oleg Butovsky, Marie-Ève Tremblay
The past decade has witnessed a revolution in our understanding of microglia. These immune cells were shown to actively remodel neuronal circuits, leading to propose new pathogenic mechanisms. To study microglial implication in the loss of synapses, the best pathological correlate of cognitive decline across chronic stress, aging, and diseases, we recently conducted ultrastructural analyses. Our work uncovered the existence of a new microglial phenotype that is rarely present under steady state conditions, in hippocampus, cerebral cortex, amygdala, and hypothalamus, but becomes abundant during chronic stress, aging, fractalkine signaling deficiency (CX3 CR1 knockout mice), and Alzheimer's disease pathology (APP-PS1 mice)...
May 2016: Glia
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