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https://www.readbyqxmd.com/read/28214109/a-novel-mutation-in-trem2-gene-causing-nasu-hakola-disease-and-review-of-the-literature
#1
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...
January 20, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28209725/soluble-trem2-induces-inflammatory-responses-and-enhances-microglial-survival
#2
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...
February 16, 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
#3
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
https://www.readbyqxmd.com/read/28185874/psychosocial-stress-on-neuroinflammation-and-cognitive-dysfunctions-in-alzheimer-s-disease-the-emerging-role-for-microglia
#4
REVIEW
Sami Piirainen, Andrew Youssef, Cai Song, Allan V Kalueff, Gary E Landreth, Tarja Malm, Li Tian
Chronic psychosocial stress is increasingly recognized as a risk factor for late-onset Alzheimer's disease (LOAD) and associated cognitive deficits. Chronic stress also primes microglia and induces inflammatory responses in the adult brain, thereby compromising synapse-supportive roles of microglia and deteriorating cognitive functions during aging. Substantial evidence demonstrates that failure of microglia to clear abnormally accumulating amyloid-beta (Aβ) peptide contributes to neuroinflammation and neurodegeneration in AD...
February 6, 2017: Neuroscience and Biobehavioral Reviews
https://www.readbyqxmd.com/read/28111922/increased-expression-of-triggering-receptor-expressed-on-myeloid-cells-1-in-the-population-with-obesity-and-insulin-resistance
#5
Saravanan Subramanian, Pradeep K Pallati, Vikrant Rai, Poonam Sharma, Devendra K Agrawal, Kalyana C Nandipati
OBJECTIVE: Triggering receptor expressed on myeloid cells (TREM)-1 has recently been recognized as one of the potent amplifiers of acute and chronic inflammation. However, the exact role of TREM-1 in regard to insulin insensitivity is unknown. METHODS: mRNA transcripts and protein expression of TREM-1, TREM-2, and TREM-1/TREM-2 ratio were examined in the tissue biopsies (liver, omentum, and subcutaneous fat) and blood samples (neutrophils and monocytes) of subjects with obesity and diabetes (SO(+) D(+) ; n = 15), subjects with obesity but not diabetes (SO(+) D(-) ; n = 7), and subjects without obesity (BMI < 30) and diabetes (SO(-) D(-) ; n = 5)...
January 23, 2017: Obesity
https://www.readbyqxmd.com/read/28100745/disease-progression-dependent-effects-of-trem2-deficiency-in-a-mouse-model-of-alzheimer-s-disease
#6
Taylor R Jay, Anna M Hirsch, Margaret L Broihier, Crystal M Miller, Lee E Neilson, Richard M Ransohoff, Bruce T Lamb, Gary E Landreth
: Neuroinflammation is an important contributor to Alzheimer's disease (AD) pathogenesis, as underscored by the recent identification of immune-related genetic risk factors for AD, including coding variants in the gene TREM2 (triggering receptor expressed on myeloid cells 2). Understanding TREM2 function promises to provide important insights into how neuroinflammation contributes to AD pathology. However, studies so far have produced seemingly conflicting results, with reports that amyloid pathology can be both decreased and increased in TREM2-deficient AD mouse models...
January 18, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28089363/pertussis-toxin-targets-the-innate-immunity-through-dap12-fcr%C3%AE-and-myd88-adaptor-proteins
#7
Vongsavanh Phongsisay, Ei'ichi Iizasa, Hiromitsu Hara, Hiroki Yoshida
Activation of the innate immunity by adjuvants, such as pertussis toxin (PTX), in the presence of autoreactive lymphocytes and antigen mimicry is sufficient to trigger autoimmunity. Toll-like, C-type lectin, and immunglobulin-like receptors play an important role in the innate immunity by sensing a variety of microbial products through several adaptor proteins, including MyD88, DAP12, and FcRγ. This study investigated the interaction between PTX and innate immune components. The direct interactions between coated PTX and receptor-fusion proteins were examined using ELISA-based binding assays...
December 30, 2016: Immunobiology
https://www.readbyqxmd.com/read/28077724/trem2-promotes-microglial-survival-by-activating-wnt-%C3%AE-catenin-pathway
#8
Honghua Zheng, Lin Jia, Chia-Chen Liu, Zhouyi Rong, Li Zhong, Longyu Yang, Xiao-Fen Chen, John D Fryer, Xin Wang, Yun-Wu Zhang, Huaxi Xu, Guojun Bu
: Triggering Receptor Expressed on Myeloid cells 2 (TREM2), expressed on myeloid cells including microglia in the central nervous system (CNS), has recently been identified as a risk factor for Alzheimer's disease (AD). TREM2 transmits intracellular signals through its trans-membrane binding partner DNAX-activating protein 12 (DAP12). Homozygous mutations inactivating TREM2 or DAP12 lead to Nasu-Hakola disease (NHD); however, how AD risk-conferring variants increase AD risk is not clear...
January 11, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28070672/opposing-effects-of-progranulin-deficiency-on-amyloid-and-tau-pathologies-via-microglial-tyrobp-network
#9
Hideyuki Takahashi, Zoe A Klein, Sarah M Bhagat, Adam C Kaufman, Mikhail A Kostylev, Tsuneya Ikezu, Stephen M Strittmatter
Progranulin (PGRN) is implicated in Alzheimer's disease (AD) as well as frontotemporal lobar degeneration. Genetic studies demonstrate an association of the common GRN rs5848 variant that results in reduced PGRN levels with increased risk for AD. However, the mechanisms by which PGRN reduction from the GRN AD risk variant or mutation exacerbates AD pathophysiology remain ill defined. Here, we show that the GRN AD risk variant has no significant effects on florbetapir positron emission tomographic amyloid imaging and cerebrospinal fluid (CSF) Aβ levels, whereas it is associated with increased CSF tau levels in human subjects of the Alzheimer's disease neuroimaging initiative studies...
January 9, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28052121/molecular-characteristics-of-high-dose-melphalan-associated-oral-mucositis-in-patients-with-multiple-myeloma-a-gene-expression-study-on-human-mucosa
#10
Mette Marcussen, Julie Støve Bødker, Heidi Søgaard Christensen, Preben Johansen, Søren Nielsen, Ilse Christiansen, Olav Jonas Bergmann, Martin Bøgsted, Karen Dybkær, Mogens Vyberg, Hans Erik Johnsen
BACKGROUND: Toxicity of the oral and gastrointestinal mucosa induced by high-dose melphalan is a clinical challenge with no documented prophylactic interventions or predictive tests. The aim of this study was to describe molecular changes in human oral mucosa and to identify biomarkers correlated with the grade of clinical mucositis. METHODS AND FINDINGS: Ten patients with multiple myeloma (MM) were included. For each patient, we acquired three buccal biopsies, one before, one at 2 days, and one at 20 days after high-dose melphalan administration...
2017: PloS One
https://www.readbyqxmd.com/read/28002825/from-common-to-rare-variants-the-genetic-component-of-alzheimer-disease
#11
Gaël Nicolas, Camille Charbonnier, Dominique Campion
Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Aβ peptide, which aggregates in AD brains, is a key player...
December 22, 2016: Human Heredity
https://www.readbyqxmd.com/read/27999880/-pathomechanisms-and-clinical-aspects-of-frontotemporal-lobar-degeneration
#12
REVIEW
K Bürger, T Arzberger, J Stephan, J Levin, D Edbauer
BACKGROUND: Frontotemporal lobar degeneration (FTLD) includes a spectrum of heterogeneous clinical and neuropathological diseases. In a strict sense this includes the behavioral variant of frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA) and both variants can be associated with amyotrophic lateral sclerosis (FTD-ALS). In a broader sense FTLD also includes progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). In recent years the strong genetic component of FTLD has become increasingly clear...
December 20, 2016: Der Nervenarzt
https://www.readbyqxmd.com/read/27995897/neurodegenerative-disease-mutations-in-trem2-reveal-a-functional-surface-and-distinct-loss-of-function-mechanisms
#13
Daniel L Kober, Jennifer M Alexander-Brett, Celeste M Karch, Carlos Cruchaga, Marco Colonna, Michael J Holtzman, Thomas J Brett
Genetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases. To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins. Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer's disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function. Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer's risk variants impact binding to a TREM2 ligand...
December 20, 2016: ELife
https://www.readbyqxmd.com/read/27974666/early-changes-in-csf-strem2-in-dominantly-inherited-alzheimer-s-disease-occur-after-amyloid-deposition-and-neuronal-injury
#14
Marc Suárez-Calvet, Miguel Ángel Araque Caballero, Gernot Kleinberger, Randall J Bateman, Anne M Fagan, John C Morris, Johannes Levin, Adrian Danek, Michael Ewers, Christian Haass
Emerging evidence supports a role for innate immunity and microglia in Alzheimer's disease (AD) pathophysiology. However, no marker related to microglia has been included in the temporal evolution models of AD. TREM2 is a transmembrane protein involved in innate immunity and is selectively expressed by microglia and genetically linked to AD and other neurodegenerative disorders. Its ectodomain is released by proteolysis as a soluble variant (sTREM2) and can be detected in the cerebrospinal fluid (CSF). In patients with autosomal dominant AD, we tested how many years before the expected symptom onset did CSF sTREM2 increase in mutation carriers (MCs) compared to noncarriers (NCs)...
December 14, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27940990/disease-progression-dependent-effects-of-trem2-deficiency-in-a-mouse-model-of-alzheimer-s-disease
#15
Taylor R Jay, Anna M Hirsch, Margaret L Broihier, Crystal M Miller, Lee E Neilson, Richard M Ransohoff, Bruce T Lamb, Gary E Landreth
: Neuroinflammation is an important contributor to Alzheimer's disease (AD) pathogenesis, as underscored by the recent identification of immune-related genetic risk factors for AD, including coding variants in the gene triggering receptor expressed on myeloid cells 2 (TREM2). Understanding TREM2 function promises to provide important insights into how neuroinflammation contributes to AD pathology. However, studies so far have produced seemingly conflicting results, with reports that amyloid pathology can be both decreased and increased in TREM2 deficient AD mouse models...
December 9, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27939925/a-candidate-regulatory-variant-at-the-trem-gene-cluster-associates-with-decreased-alzheimer-s-disease-risk-and-increased-treml1-and-trem2-brain-gene-expression
#16
Minerva M Carrasquillo, Mariet Allen, Jeremy D Burgess, Xue Wang, Samantha L Strickland, Shivani Aryal, Joanna Siuda, Michaela L Kachadoorian, Christopher Medway, Curtis S Younkin, Asha Nair, Chen Wang, Pritha Chanana, Daniel Serie, Thuy Nguyen, Sarah Lincoln, Kimberly G Malphrus, Kevin Morgan, Todd E Golde, Nathan D Price, Charles C White, Philip L De Jager, David A Bennett, Yan W Asmann, Julia E Crook, Ronald C Petersen, Neill R Graff-Radford, Dennis W Dickson, Steven G Younkin, Nilüfer Ertekin-Taner
INTRODUCTION: We hypothesized that common Alzheimer's disease (AD)-associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression. METHODS: Expression microarrays on temporal cortex and cerebellum from ∼400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis. RESULTS: A variant within a DNase hypersensitive site 5' of TREM2, rs9357347-C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6...
December 8, 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/27922847/apolipoprotein-e-metabolism-and-functions-in-brain-and-its-role-in-alzheimer-s-disease
#17
Fan Liao, Hyejin Yoon, Jungsu Kim
PURPOSE OF REVIEW: APOE4 genotype is the strongest genetic risk factor for Alzheimer's disease. Prevailing evidence suggests that amyloid β plays a critical role in Alzheimer's disease. The objective of this article is to review the recent findings about the metabolism of apolipoprotein E (ApoE) and amyloid β and other possible mechanisms by which ApoE contributes to the pathogenesis of Alzheimer's disease. RECENT FINDINGS: ApoE isoforms have differential effects on amyloid β metabolism...
February 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/27904823/expression-of-gp91phox-and-p22phox-catalytic-subunits-of-nadph-oxidase-on-microglia-in-nasu-hakola-disease-brains
#18
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
#19
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/27887626/expression-and-processing-analyses-of-wild-type-and-p-r47h-trem2-variant-in-alzheimer-s-disease-brains
#20
Li Ma, Mariet Allen, Nobutaka Sakae, Nilufer Ertekin-Taner, Neill R Graff-Radford, Dennis W Dickson, Steven G Younkin, Daniel Sevlever
BACKGROUND: Genetic analyses showed that the triggering receptor expressed in myeloid cells 2 (TREM2) p.R47H variant increases the risk for Alzheimer's disease (AD). The question of whether the p.R47H mutation affects expression or function of the receptor remains unanswered. To address this question we quantified mRNA and analyzed protein profiles of WT and p.R47H TREM2 in human brains. METHODS: Quantitative real-time PCR (qPCR) was performed using 2 sets of primers one that detects all TREM2 mRNA isoforms and one specific for the alternative spliced isoform (TREM2alt) that encodes for the extracellular domain (soluble TREM2)...
November 25, 2016: Molecular Neurodegeneration
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