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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
E Y Scott, M C T Penedo, J D Murray, C J Finno
Equine cerebellar abiotrophy (CA) is a hereditary neurodegenerative disease that affects the Purkinje neurons of the cerebellum and causes ataxia in Arabian foals. Signs of CA are typically first recognized either at birth to any time up to 6 months of age. CA is inherited as an autosomal recessive trait and is associated with a single nucleotide polymorphism (SNP) on equine chromosome 2 (13074277G>A), located in the fourth exon of TOE1 and in proximity to MUTYH on the antisense strand. We hypothesize that unraveling the functional consequences of the CA SNP using RNA-seq will elucidate the molecular pathways underlying the CA phenotype...
October 5, 2016: Cerebellum
Animesh Alexander Raha, James W Henderson, Simon R W Stott, Romina Vuono, Simona Foscarin, Robert P Friedland, Shahid H Zaman, Ruma Raha-Chowdhury
Neuroinflammation and activation of innate immunity are early events in neurodegenerative diseases including Alzheimer's disease (AD). Recently, a rare mutation in the gene Triggering receptor expressed on myeloid cells 2 (TREM2) has been associated with a substantial increase in the risk of developing late onset AD. To uncover the molecular mechanisms underlying this association, we investigated the RNA and protein expression of TREM2 in APP/PS1 transgenic mice. Our findings suggest that TREM2 not only plays a critical role in inflammation, but is also involved in neuronal cell survival and in neurogenesis...
September 20, 2016: Journal of Alzheimer's Disease: JAD
Cyril Pottier, Thomas A Ravenscroft, Patricia H Brown, NiCole A Finch, Matt Baker, Meeia Parsons, Yan W Asmann, Yingxue Ren, Elizabeth Christopher, Denise Levitch, Marka van Blitterswijk, Carlos Cruchaga, Dominique Campion, Gaël Nicolas, Anne-Claire Richard, Rita Guerreiro, Jose T Bras, Stephan Zuchner, Michael A Gonzalez, Guojun Bu, Steven Younkin, David S Knopman, Keith A Josephs, Joseph E Parisi, Ronald C Petersen, Nilüfer Ertekin-Taner, Neill R Graff-Radford, Bradley F Boeve, Dennis W Dickson, Rosa Rademakers
We aimed to identify new candidate genes potentially involved in early-onset Alzheimer's disease (EOAD). Exome sequencing was conducted on 45 EOAD patients with either a family history of Alzheimer's disease (AD, <65 years) or an extremely early age at the onset (≤55 years) followed by multiple variant filtering according to different modes of inheritance. We identified 29 candidate genes potentially involved in EOAD, of which the gene TYROBP, previously implicated in AD, was selected for genetic and functional follow-up...
August 8, 2016: Neurobiology of Aging
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
Heather M Wilkins, Scott J Koppel, Ian W Weidling, Nairita Roy, Lauren N Ryan, John A Stanford, Russell H Swerdlow
Mitochondria and mitochondrial debris are found in the brain's extracellular space, and extracellular mitochondrial components can act as damage associated molecular pattern (DAMP) molecules. To characterize the effects of potential mitochondrial DAMP molecules on neuroinflammation, we injected either isolated mitochondria or mitochondrial DNA (mtDNA) into hippocampi of C57BL/6 mice and seven days later measured markers of inflammation. Brains injected with whole mitochondria showed increased Tnfα and decreased Trem2 mRNA, increased GFAP protein, and increased NFκB phosphorylation...
August 25, 2016: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
Filip Petković, Iain L Campbell, Berta Gonzalez, Bernardo Castellano
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Interleukin (IL)-6 is a pleiotropic cytokine with a potential role in MS. Here we used transgenic mice with astrocyte-targeted production of IL-6 (GFAP-IL6Tg) to study the effect of IL-6 in the cuprizone-induced demyelination paradigm, which is an experimental model of de- and re-myelination, both hallmarks of MS. Our results demonstrated that cuprizone-treated GFAP-IL6Tg mice showed a significant reduction in astroglial and especially microglial activation/accumulation in the corpus callosum in comparison with the corresponding cuprizone-treated wild type (WT)...
August 18, 2016: Glia
Adam R Smith, Rebecca G Smith, Daniel Condliffe, Eilis Hannon, Leonard Schalkwyk, Jonathan Mill, Katie Lunnon
Although mutations within the TREM2 gene have been robustly associated with Alzheimer's disease, it is not known whether alterations in the regulation of this gene are also involved in pathogenesis. Here, we present data demonstrating increased DNA methylation in the superior temporal gyrus in Alzheimer's disease brain at a CpG site located 289 bp upstream of the transcription start site of the TREM2 gene in 3 independent study cohorts using 2 different technologies (Illumina Infinium 450K methylation beadchip and pyrosequencing)...
July 16, 2016: Neurobiology of Aging
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
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
Teng Jiang, Jian-Kang Hou, Qing Gao, Jin-Tai Yu, Jun-Shan Zhou, Hong-Dong Zhao, Ying-Dong Zhang
We recently revealed that p.H157Y (rs2234255), a rare coding variant of TREM2, was associated with Alzheimer's disease (AD) susceptibility in Han Chinese. Contrastingly, although p.H157Y was previously identified in both AD cases and controls by several sequencing studies, no association of this variant with disease susceptibility was reported. To gain a credible conclusion on the association between p.H157Y and AD risk, a meta-analysis involving 7,102 cases and 7,408 controls was conducted. Our results indicated that p...
August 7, 2016: Current Neurovascular Research
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
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
Juan Domingo Gispert, Marc Suárez-Calvet, Gemma C Monté, Alan Tucholka, Carles Falcon, Santiago Rojas, Lorena Rami, Raquel Sánchez-Valle, Albert Lladó, Gernot Kleinberger, Christian Haass, José Luis Molinuevo
INTRODUCTION: TREM2 is involved in the regulation of inflammatory response and phagocytosis. A soluble fragment (sTREM2) is often found abnormally increased in cerebrospinal fluid (CSF) in Alzheimer's disease (AD). METHODS: Of the total, 114 participants (45 control, 19 preclinical, 27 mild cognitive impairment [MCI], and 23 AD) underwent CSF sTREM2 determination and magnetic resonance imaging (MRI). We studied the association between CSF sTREM2, gray matter volume, and water motion diffusivity and anisotropy across groups...
July 13, 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
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
Yuhai Zhao, Vivian Jaber, Walter J Lukiw
One prominent and distinguishing feature of progressive, age-related neurological diseases such as Alzheimer's disease (AD) and prion disease (PrD) is the gradual accumulation of amyloids into dense, insoluble end-stage protein aggregates. These polymorphic proteolipid lesions are known to contribute to immunogenic and inflammatory pathology in these insidious and fatal disorders of the human central nervous system (CNS). For example, the evolution of self-aggregating amyloid-beta (Aβ) peptides, such as the 42 amino acid Aβ42 peptide monomer into higher order aggregates are largely due to: (1) the inability of natural processes to clear them from the cellular environment; and/or (2) the overproduction of these amyloid monomers which rapidly mature into higher order oligomers, fibrils and insoluble, end-stage senile plaques...
2016: Frontiers in Aging Neuroscience
Luise Borufka, Erik Volmer, Sarah Müller, Robby Engelmann, Horst Nizze, Saleh Ibrahim, Robert Jaster
OBJECTIVES: MRL/MpJ mice spontaneously develop an autoimmune pancreatitis (AIP) and are widely used as a model to study the genetic, molecular and immunological basis of the disease. Here, we have addressed the question whether distinctive features of their dendritic cells (DCs) may predispose MRL/MpJ mice to the chronic inflammation. METHODS: Pancreatic lesions were analyzed employing histological methods. Cohorts of young (healthy) MRL/MpJ mice, adult (sick) individuals, and AIP-resistant CAST/EiJ mice were used to establish cultures of bone marrow (BM)-derived conventional DCs (cDCs)...
June 23, 2016: Oncotarget
Friederike Schröter, Kristel Sleegers, Elise Cuyvers, Martina Bohndorf, Wasco Wruck, Christine Van Broeckhoven, James Adjaye
Human lymphoblast cells from a male patient diagnosed with Alzheimer's disease (AD) expressing the TREM2 p.R47H variant were used to generate integration-free induced pluripotent stem (iPS) cells employing episomal plasmids expressing OCT4, SOX2, NANOG, LIN28, c-MYC and L-MYC. The iPS cells retained the TREM2 mutation, and were defined as pluripotent based on (i) expression of pluripotent-associated markers, (ii) embryoid body-based differentiation into cell types representative of the three germ layers and (iii) the similarity between the transcriptomes of the iPS cell line and the human embryonic stem cell line H1 with a Pearson correlation of 0...
January 2016: Stem Cell Research
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