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TREM2 Parkinson

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
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
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...
April 2018: Experimental Neurology
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
Vanessa Porrini, Mariana Mota, Edoardo Parrella, Arianna Bellucci, Marina Benarese, Lara Faggi, Paolo Tonin, Pier F Spano, Marina Pizzi
The impact of neuroinflammation and microglial activation to Parkinson's disease (PD) progression is still debated. Post-mortem analysis of PD brains has shown that neuroinflammation and microgliosis are key features of end-stage disease. However, microglia neuroimaging studies and evaluation of cerebrospinal fluid (CSF) cytokines in PD patients at earlier stages do not support the occurrence of a pronounced neuroinflammatory process. PD animal models recapitulating the motor and non-motor features of the disease, and the slow and progressive neuropathology, can be of great advantage in understanding whether and how neuroinflammation associates with the onset of symptoms and neuronal loss...
2017: Frontiers in Aging Neuroscience
Efthimios Dardiotis, Vasileios Siokas, Eva Pantazi, Maria Dardioti, Dimitrios Rikos, Georgia Xiromerisiou, Aikaterini Markou, Dimitra Papadimitriou, Matthaios Speletas, Georgios M Hadjigeorgiou
Nasu-hakola disease (NHD) is a rare disease characterized by bone cysts and fractures, frontal lobe syndrome, and progressive presenile dementia. NHD may be the prototype of primary microglial disorders of the CNS or, as they have been coined, "microgliopathies". Mutations in TREM2 and TYROBP genes are known to cause NHD. Interestingly, recent evidence-associated rare genetic variants of TREM2 gene with increased risk of Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Parkinson's disease...
May 2017: Neurobiology of Aging
Jie Han, Miaomiao Wang, Manru Ren, Haiyan Lou
Recent laboratory and gene sequencing data suggest that variations in receptors called the "triggering-receptors-expressed-on-myeloid-cells" (TREMs) are implicated in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and frontotemporal lobar degeneration. TREM receptors are thought to play a critical role in regulating the immune system, inflammation, and certain cellular functions. One TREM, in particular, TREM2, is highly expressed on cells of the myeloid lineage. The binding of TREM2 to the adapter protein, DNAX activating protein of 12 kD (DAP12), in microglial cells has been shown to modulate phagocytosis within the nervous system...
April 2017: International Journal of Neuroscience
Gail Chan, Charles C White, Phoebe A Winn, Maria Cimpean, Joseph M Replogle, Laura R Glick, Nicole E Cuerdon, Katie J Ryan, Keith A Johnson, Julie A Schneider, David A Bennett, Lori B Chibnik, Reisa A Sperling, Philip L De Jager, Elizabeth M Bradshaw
OBJECTIVE: Given evidence from genetic studies, we hypothesized that there may be a shared component to the role of myeloid function in Parkinson and Alzheimer disease (PD and AD) and assessed whether PD susceptibility variants influenced protein expression of well-established AD-associated myeloid genes in human monocytes. METHODS: We repurposed data in which AD-related myeloid proteins CD33, TREM1, TREM2, TREML2, TYROBP, and PTK2B were measured by flow cytometry in monocytes from 176 participants of the PhenoGenetic Project (PGP) and Harvard Aging Brain Study...
August 2016: Neurology. Genetics
Ronald L Walton, Alexandra I Soto-Ortolaza, Melissa E Murray, Oswaldo Lorenzo-Betancor, Kotaro Ogaki, Michael G Heckman, Sruti Rayaprolu, Rosa Rademakers, Nilüfer Ertekin-Taner, Ryan J Uitti, Jay A van Gerpen, Zbigniew K Wszolek, Glenn E Smith, Kejal Kantarci, Val J Lowe, Joseph E Parisi, David T Jones, Rodolfo Savica, Jonathan Graff-Radford, David S Knopman, Ronald C Petersen, Neill R Graff-Radford, Tanis J Ferman, Dennis W Dickson, Bradley F Boeve, Owen A Ross, Catherine Labbé
Dementia with Lewy bodies (DLB) is the second leading cause of neurodegenerative dementia in the elderly and is clinically characterized by the presence of cognitive decline, parkinsonism, REM sleep behavior disorder, and visual hallucinations.(1,2) At autopsy, α-synuclein-positive Lewy-related pathology is observed throughout the brain. Concomitant Alzheimer disease-related pathology including amyloid plaques and, to a lesser degree, neurofibrillary tangles are often present.(2) The clinical characteristics of DLB share overlapping features with Alzheimer disease dementia (AD) and Parkinson disease (PD)...
August 2016: Neurology. Genetics
José Fidel Baizabal-Carvallo, Joseph Jankovic
Frontotemporal dementia (FTD) refers to a group of clinically and genetically heterogeneous neurodegenerative disorders that are a common cause of adult-onset behavioural and cognitive impairment. FTD often presents in combination with various hyperkinetic or hypokinetic movement disorders, and evidence suggests that various genetic mutations underlie these different presentations. Here, we review the known syndromatic-genetic correlations in FTD. Although no direct genotype-phenotype correlations have been identified, mutations in multiple genes have been associated with various presentations...
March 2016: Nature Reviews. Neurology
Yuka Atagi, Chia-Chen Liu, Meghan M Painter, Xiao-Fen Chen, Christophe Verbeeck, Honghua Zheng, Xia Li, Rosa Rademakers, Silvia S Kang, Huaxi Xu, Steven Younkin, Pritam Das, John D Fryer, Guojun Bu
Several heterozygous missense mutations in the triggering receptor expressed on myeloid cells 2 (TREM2) have recently been linked to risk for a number of neurological disorders including Alzheimer disease (AD), Parkinson disease, and frontotemporal dementia. These discoveries have re-ignited interest in the role of neuroinflammation in the pathogenesis of neurodegenerative diseases. TREM2 is highly expressed in microglia, the resident immune cells of the central nervous system. Along with its adaptor protein, DAP12, TREM2 regulates inflammatory cytokine release and phagocytosis of apoptotic neurons...
October 23, 2015: Journal of Biological Chemistry
Guiyou Liu, Yongquan Liu, Qinghua Jiang, Yongshuai Jiang, Rennan Feng, Liangcai Zhang, Zugen Chen, Keshen Li, Jiafeng Liu
A rare TREM2 missense mutation (rs75932628-T) was reported to confer a significant Alzheimer's disease (AD) risk. A recent study indicated no evidence of the involvement of this variant in Parkinson's disease (PD). Here, we used the genetic and expression data to reinvestigate the potential association between TREM2 and PD susceptibility. In stage 1, using 10 independent studies (N = 89,157; 8787 cases and 80,370 controls), we conducted a subgroup meta-analysis. We identified a significant association between rs75932628 and PD (P = 3...
September 2016: Molecular Neurobiology
Olena Korvatska, James B Leverenz, Suman Jayadev, Pamela McMillan, Irina Kurtz, Xindi Guo, Malia Rumbaugh, Mark Matsushita, Santhosh Girirajan, Michael O Dorschner, Kostantin Kiianitsa, Chang-En Yu, Zoran Brkanac, Gwenn A Garden, Wendy H Raskind, Thomas D Bird
IMPORTANCE: The R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders. OBJECTIVE: To investigate a large family with late-onset AD (LOAD), in which R47H cosegregated with 75% of cases. DESIGN, SETTING, AND PARTICIPANTS: This study includes genetic and pathologic studies of families with LOAD from 1985 to 2014...
August 2015: JAMA Neurology
Yongping Chen, Xueping Chen, Xiaoyan Guo, Wei Song, Bei Cao, Qianqian Wei, Ruwei Ou, Bi Zhao, Hui-Fang Shang
Although rs75932628 in triggering receptor expressed on myeloid cells 2 (TREM2) was shown to increase the risk for Alzheimer's disease, there is no agreement on the association between this variant and the risk for Parkinson's disease (PD). Considering the overlapping of clinical manifestation and pathologic characteristics of PD and multiple system atrophy (MSA), we conducted a large-sample study to investigate the associations between this variant and these two neurodegenerative diseases in a Chinese population...
October 2015: Neurological Sciences
Christina M Lill, Aina Rengmark, Lasse Pihlstrøm, Isabella Fogh, Aleksey Shatunov, Patrick M Sleiman, Li-San Wang, Tian Liu, Christina F Lassen, Esther Meissner, Panos Alexopoulos, Andrea Calvo, Adriano Chio, Nil Dizdar, Frank Faltraco, Lars Forsgren, Julia Kirchheiner, Alexander Kurz, Jan P Larsen, Maria Liebsch, Jan Linder, Karen E Morrison, Hans Nissbrandt, Markus Otto, Jens Pahnke, Amanda Partch, Gabriella Restagno, Dan Rujescu, Cathrin Schnack, Christopher E Shaw, Pamela J Shaw, Hayrettin Tumani, Ole-Bjørn Tysnes, Otto Valladares, Vincenzo Silani, Leonard H van den Berg, Wouter van Rheenen, Jan H Veldink, Ulman Lindenberger, Elisabeth Steinhagen-Thiessen, Stefan Teipel, Robert Perneczky, Hakon Hakonarson, Harald Hampel, Christine A F von Arnim, Jørgen H Olsen, Vivianna M Van Deerlin, Ammar Al-Chalabi, Mathias Toft, Beate Ritz, Lars Bertram
A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis...
December 2015: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Sara Ortega-Cubero, Oswaldo Lorenzo-Betancor, Elena Lorenzo, José A G Agúndez, Félix J Jiménez-Jiménez, Owen A Ross, Isabel Wurster, Carina Mielke, Juei-Jueng Lin, Francisco Coria, Jordi Clarimon, Mario Ezquerra, Laura Brighina, Grazia Annesi, Hortensia Alonso-Navarro, Elena García-Martin, Alex Gironell, Maria J Marti, Kuo-Chu Yueh, Zbigniew K Wszolek, Manu Sharma, Daniela Berg, Rejko Krüger, Maria A Pastor, Pau Pastor
INTRODUCTION: Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysiology is not clearly understood, however there is growing evidence showing common etiologic factors with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (AD, PD). Recently, a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis (ALS)...
March 2015: Parkinsonism & related Disorders
Jun-Ichi Satoh, Naohiro Asahina, Shouta Kitano, Yoshihiro Kino
Microglia are resident mononuclear phagocytes that play a principal role in the maintenance of normal tissue homeostasis in the central nervous system (CNS). Microglia, rapidly activated in response to proinflammatory stimuli, are accumulated in brain lesions of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. The E26 transformation-specific (ETS) family transcription factor PU.1/Spi1 acts as a master regulator of myeloid and lymphoid development. PU.1-deficient mice show a complete loss of microglia, indicating that PU...
2014: Gene Regulation and Systems Biology
L-F Lue, C Schmitz, D G Walker
Microglia play major roles in initiation, coordination and execution of innate immunity in the brain. In the adult brain, these include maintenance of homeostasis, neuron and tissue repair, and eliminating infectious agents, apoptotic cells, and misfolded proteins. Some of these activities are accompanied by inflammatory reactions; and others are performed with no inflammatory effects. Under normal conditions, triggering receptor expressed on myeloid cells 2 (TREM2) belongs to the second category. It pairs with the adaptor protein DNAX-activating protein of 12kDa (DAP12) to induce phagocytosis of apoptotic neurons without inflammatory responses, and to regulate Toll-like receptor-mediated inflammatory responses, and microglial activation...
August 27, 2015: Neuroscience
Lih-Fen Lue, Christopher T Schmitz, Geidy Serrano, Lucia I Sue, Thomas G Beach, Douglas G Walker
Triggering receptor expressed by myeloid cells 2 (TREM2), a member of the immunoglobulin superfamily, has anti-inflammatory phagocytic function in myeloid cells. Several studies have shown that TREM2 gene variant rs75932628-T increased the risks for Alzheimer's disease (AD), Parkinson's disease, frontotemporal dementia and amyotrophic lateral sclerosis. It has been suggested that the risks could be resulted from the loss of TREM2 function caused by the mutation. Indeed, new evidence showed that several mutations in the immunoglobulin-like V-region led to low cell surface expression of TREM2 and reduced phagocytic function...
July 2015: Brain Pathology
Gernot Kleinberger, Yoshinori Yamanishi, Marc Suárez-Calvet, Eva Czirr, Ebba Lohmann, Elise Cuyvers, Hanne Struyfs, Nadine Pettkus, Andrea Wenninger-Weinzierl, Fargol Mazaheri, Sabina Tahirovic, Alberto Lleó, Daniel Alcolea, Juan Fortea, Michael Willem, Sven Lammich, José L Molinuevo, Raquel Sánchez-Valle, Anna Antonell, Alfredo Ramirez, Michael T Heneka, Kristel Sleegers, Julie van der Zee, Jean-Jacques Martin, Sebastiaan Engelborghs, Asli Demirtas-Tatlidede, Henrik Zetterberg, Christine Van Broeckhoven, Hakan Gurvit, Tony Wyss-Coray, John Hardy, Marco Colonna, Christian Haass
Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to Nasu-Hakola disease, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and FTD-like syndrome without bone involvement. TREM2 is an innate immune receptor preferentially expressed by microglia and is involved in inflammation and phagocytosis. Whether and how TREM2 missense mutations affect TREM2 function is unclear. We report that missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases, and impair the phagocytic activity of TREM2-expressing cells...
July 2, 2014: Science Translational Medicine
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