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https://www.readbyqxmd.com/read/27922847/apolipoprotein-e-metabolism-and-functions-in-brain-and-its-role-in-alzheimer-s-disease
#1
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...
December 5, 2016: 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
#2
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
#3
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
#4
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
https://www.readbyqxmd.com/read/27871212/contributions-of-triggering-receptor-expressed-on-myeloid-cells-2-to-neurological-diseases
#5
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...
November 22, 2016: International Journal of Neuroscience
https://www.readbyqxmd.com/read/27859676/microglia-and-brain-macrophages-an-update
#6
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/27814610/molecular-mechanisms-of-the-genetic-risk-factors-in-pathogenesis-of-alzheimer-disease
#7
Kunihiko Kanatsu, Taisuke Tomita
Alzheimer disease (AD) is a neurodegenerative disease characterized by the extensive deposition of senile plaques and neurofibrillary tangles. Until recently, only the APOE gene had been known as a genetic risk factor for late-onset AD (LOAD), which accounts for more than 95% of all AD cases. However, in addition to this well-established genetic risk factor, genome-wide association studies have identified several single nucleotide polymorphisms as genetic risk factors of LOAD, such as PICALM and BIN1. In addition, whole genome sequencing and exome sequencing have identified rare variants associated with LOAD, including TREM2...
January 1, 2017: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/27798193/trem2-dap12-signal-elicits-proinflammatory-response-in-microglia-and-exacerbates-neuropathic-pain
#8
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/27789408/lymphoblast-derived-integration-free-ips-cell-line-from-a-female-67-year-old-alzheimer-s-disease-patient-with-trem2-r47h-missense-mutation
#9
Friederike Schröter, Kristel Sleegers, Elise Cuyvers, Martina Bohndorf, Wasco Wruck, Christine Van Broeckhoven, James Adjaye
Human lymphoblast cells from a female patient diagnosed with Alzheimer's disease (AD) possessing the missense mutation TREM2 p.R47H were used to generate integration-free induced pluripotent stem cells (iPSCs) employing episomal plasmids expressing OCT4, SOX2, NANOG, LIN28, c-MYC and L-MYC. The iPSCs 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 iPSC line and the human embryonic stem cell line H1 with a Pearson correlation of 0...
October 20, 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27769848/trems-in-alzheimer-s-disease-genetic-and-clinical-investigations
#10
REVIEW
Jia Cheng, XiaoFeng Guo, Tian Zhang, Li Zhong, GuoJun Bu, XiaoFen Chen
Triggering receptor expressed on myeloid cells (TREMs) receptors constitute a family modulators in human innate immunity system that encode by a gene cluster. Rare variants in TREM2 were reported to be associated with significant Alzheimer's disease (AD) risk. However, inconsistent results were also reported in some studies of Non-European descents. Recently, the other TREM family members are also considered to involve in AD and cerebrospinal fluid (CSF) soluble form of TREM2 (sTREM2) levels has also been associated with respond to progression of disease...
December 1, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/27717139/vps35-dependent-recycling-of-trem2-regulates-microglial-function
#11
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
#12
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/27709457/defining-trends-in-global-gene-expression-in-arabian-horses-with-cerebellar-abiotrophy
#13
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
https://www.readbyqxmd.com/read/27662313/neuroprotective-effect-of-trem-2-in-aging-and-alzheimer-s-disease-model
#14
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
https://www.readbyqxmd.com/read/27658901/tyrobp-genetic-variants-in-early-onset-alzheimer-s-disease
#15
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
https://www.readbyqxmd.com/read/27589997/rare-trem2-variants-associated-with-alzheimer-s-disease-display-reduced-cell-surface-expression
#16
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
https://www.readbyqxmd.com/read/27562848/extracellular-mitochondria-and-mitochondrial-components-act-as-damage-associated-molecular-pattern-molecules-in-the-mouse-brain
#17
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...
December 2016: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/27535761/astrocyte-targeted-production-of-interleukin-6-reduces-astroglial-and-microglial-activation-in-the-cuprizone-demyelination-model-implications-for-myelin-clearance-and-oligodendrocyte-maturation
#18
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
https://www.readbyqxmd.com/read/27522519/increased-dna-methylation-near-trem2-is-consistently-seen-in-the-superior-temporal-gyrus-in-alzheimer-s-disease-brain
#19
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
https://www.readbyqxmd.com/read/27520774/alzheimer-s-disease-associated-trem2-variants-exhibit-either-decreased-or-increased-ligand-dependent-activation
#20
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
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