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Microglia apoE

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https://www.readbyqxmd.com/read/29803222/serum-amyloid-a-primes-microglia-for-atp-dependent-interleukin-1%C3%AE-release
#1
Laura Facci, Massimo Barbierato, Morena Zusso, Stephen D Skaper, Pietro Giusti
BACKGROUND: Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves production of acute-phase proteins, including serum amyloid A (SAA). Interleukin-1β (IL-1β), a master regulator of neuroinflammation produced by activated inflammatory cells of the myeloid lineage, in particular microglia, plays a key role in the pathogenesis of acute and chronic diseases of the peripheral nervous system and CNS. IL-1β release is promoted by ATP acting at the purinergic P2X7 receptor (P2X7 R) in cells primed with toll-like receptor (TLR) ligands...
May 26, 2018: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29794134/molecular-basis-for-the-loss-of-function-effects-of-the-alzheimer-s-disease-associated-r47h-variant-of-the-immune-receptor-trem2
#2
Athena Sudom, Santosh Talreja, Jean Danao, Eric Bragg, Rob Kegel, Xiaoshan Min, Nikolai Sharkov, Edoardo Marcora, Steve Thibault, Jodi Bradley, Steve Wood, Ai-Ching Lim, Hang Chen, Songli Wang, Ian N Foltz, Shilpa Sambashivan, Zhulun Wang
Triggering receptor expressed on myeloid cells-2 (TREM2) is an immune receptor expressed on the surface of microglia, macrophages, dendritic cells, and osteoclasts. The R47H TREM2 variant is a significant risk factor for late-onset Alzheimer's disease (AD), and the molecular basis of R47H TREM2 loss-of-function is an emerging area of TREM2 biology. Here, we report three high-resolution structures of the extracellular ligand-binding domains (ECD) of R47H TREM2, apo wild-type (WT), and phosphatidylserine (PS)-bound WT TREM2 at 1...
May 24, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29784049/identification-and-therapeutic-modulation-of-a-pro-inflammatory-subset-of-disease-associated-microglia-in-alzheimer-s-disease
#3
Srikant Rangaraju, Eric B Dammer, Syed Ali Raza, Priyadharshini Rathakrishnan, Hailian Xiao, Tianwen Gao, Duc M Duong, Michael W Pennington, James J Lah, Nicholas T Seyfried, Allan I Levey
BACKGROUND: Disease-associated-microglia (DAM) represent transcriptionally-distinct and neurodegeneration-specific microglial profiles with unclear significance in Alzheimer's disease (AD). An understanding of heterogeneity within DAM and their key regulators may guide pre-clinical experimentation and drug discovery. METHODS: Weighted co-expression network analysis (WGCNA) was applied to existing microglial transcriptomic datasets from neuroinflammatory and neurodegenerative disease mouse models to identify modules of highly co-expressed genes...
May 21, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29705945/could-alzheimer-s-disease-originate-in-the-periphery-and-if-so-how-so
#4
REVIEW
Gerwyn Morris, Michael Berk, Michael Maes, Basant K Puri
The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD...
April 29, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29625180/a%C3%AE-oligomer-uptake-and-the-resulting-inflammatory-response-in-adult-human-astrocytes-are-precluded-by-an-anti-a%C3%AE-single-chain-variable-fragment-in-combination-with-an-apoe-mimetic-peptide
#5
Laia Montoliu-Gaya, Sandra D Mulder, Maaike A C Herrebout, Johannes C Baayen, Sandra Villegas, Robert Veerhuis
An imbalance between production and clearance of soluble amyloid-β (Aβ) initiates the pathological process in sporadic Alzheimer's disease (AD). Aβ-specific antibodies seemed promising as therapeutic option in AD mouse models. In patients, however, vascular side-effects and Aβ-antibody complex-induced microglial and/or perivascular macrophage inflammatory responses were encountered. To prevent inflammatory reactions, we designed a single chain variable fragment (scFv-h3D6), based on monoclonal antibody bapineuzumab (mAb-h3D6), but lacking the Fc region...
June 2018: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29563219/small-molecule-inducers-of-abca1-and-apoe-that-act-through-indirect-activation-of-the-lxr-pathway
#6
Jianjia Fan, Rui Qi Zhao, Cameron Parro, Wenchen Zhao, Hsien-Ya Chou, Jerome Robert, Tarek Z Deeb, Carina Raynoschek, Samantha Barichievy, Ola Engkvist, Marcello Maresca, Ryan Hicks, Johan Meuller, Stephen J Moss, Nicholas J Brandon, Michael W Wood, Iva Kulic, Cheryl L Wellington
apoE is the primary lipid carrier within the CNS and the strongest genetic risk factor for late onset Alzheimer's disease (AD). apoE is primarily lipidated via ABCA1, and both are under transcriptional regulation by the nuclear liver X receptor (LXR). Considerable evidence from genetic (using ABCA1 overexpression) and pharmacological (using synthetic LXR agonists) studies in AD mouse models suggests that increased levels of lipidated apoE can improve cognitive performance and, in some strains, can reduce amyloid burden...
May 2018: Journal of Lipid Research
https://www.readbyqxmd.com/read/29411406/apoe-%C3%AE%C2%B54-is-also-required-in-trem2-r47h-variant-carriers-for-alzheimer-s-disease-to-develop
#7
LETTER
C E Murray, A King, C Troakes, A Hodges, T Lashley
No abstract text is available yet for this article.
February 7, 2018: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/29376871/retinoic-acid-enhances-apolipoprotein-e-synthesis-in-human-macrophages
#8
Vera Clemens, Francesca Regen, Nathalie Le Bret, Isabella Heuser, Julian Hellmann-Regen
Apolipoprotein E (ApoE) represents a pivotal target in Alzheimer's disease (AD) and is modulated through retinoic acid (RA), an endogenous neuroprotective and anti-inflammatory compound. A major source of ApoE are microglia, which are pathologically activated in AD. Activated microglia are known to block RA signaling. This suggests a vicious cycle between inflammation, RA signaling, and ApoE homeostasis in AD pathogenesis. To test this hypothesis, we investigated effects of RA and proinflammatory activation on ApoE synthesis in primary human macrophage-derived microglial-like cells...
2018: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29038051/integrated-approach-reveals-diet-apoe-genotype-and-sex-affect-immune-response-in-app-mice
#9
Kyong Nyon Nam, Cody M Wolfe, Nicholas F Fitz, Florent Letronne, Emilie L Castranio, Anais Mounier, Jonathan Schug, Iliya Lefterov, Radosveta Koldamova
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that is influenced by genetic and environmental risk factors, such as inheritance of ε4 allele of APOE (APOE4), sex and diet. Here, we examined the effect of high fat diet (HFD) on amyloid pathology and expression profile in brains of AD model mice expressing human APOE isoforms (APP/E3 and APP/E4 mice). APP/E3 and APP/E4 mice were fed HFD or Normal diet for 3months. We found that HFD significantly increased amyloid plaques in male and female APP/E4, but not in APP/E3 mice...
January 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28959956/apoe4-markedly-exacerbates-tau-mediated-neurodegeneration-in-a-mouse-model-of-tauopathy
#10
Yang Shi, Kaoru Yamada, Shane Antony Liddelow, Scott T Smith, Lingzhi Zhao, Wenjie Luo, Richard M Tsai, Salvatore Spina, Lea T Grinberg, Julio C Rojas, Gilbert Gallardo, Kairuo Wang, Joseph Roh, Grace Robinson, Mary Beth Finn, Hong Jiang, Patrick M Sullivan, Caroline Baufeld, Michael W Wood, Courtney Sutphen, Lena McCue, Chengjie Xiong, Jorge L Del-Aguila, John C Morris, Carlos Cruchaga, Anne M Fagan, Bruce L Miller, Adam L Boxer, William W Seeley, Oleg Butovsky, Ben A Barres, Steven M Paul, David M Holtzman
APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice...
September 28, 2017: Nature
https://www.readbyqxmd.com/read/28939905/expression-and-differential-responsiveness-of-central-nervous-system-glial-cell-populations-to-the-acute-phase-protein-serum-amyloid-a
#11
Massimo Barbierato, Mila Borri, Laura Facci, Morena Zusso, Stephen D Skaper, Pietro Giusti
Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves hepatic production of acute-phase proteins, including serum amyloid A (SAA). Extrahepatically, SAA immunoreactivity is found in axonal myelin sheaths of cortex in Alzheimer's disease and multiple sclerosis (MS), although its cellular origin is unclear. We examined the responses of cultured rat cortical astrocytes, microglia and oligodendrocyte precursor cells (OPCs) to master pro-inflammatory cytokine tumour necrosis factor (TNF)-α and lipopolysaccaride (LPS)...
September 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28930663/the-trem2-apoe-pathway-drives-the-transcriptional-phenotype-of-dysfunctional-microglia-in-neurodegenerative-diseases
#12
Susanne Krasemann, Charlotte Madore, Ron Cialic, Caroline Baufeld, Narghes Calcagno, Rachid El Fatimy, Lien Beckers, Elaine O'Loughlin, Yang Xu, Zain Fanek, David J Greco, Scott T Smith, George Tweet, Zachary Humulock, Tobias Zrzavy, Patricia Conde-Sanroman, Mar Gacias, Zhiping Weng, Hao Chen, Emily Tjon, Fargol Mazaheri, Kristin Hartmann, Asaf Madi, Jason D Ulrich, Markus Glatzel, Anna Worthmann, Joerg Heeren, Bogdan Budnik, Cynthia Lemere, Tsuneya Ikezu, Frank L Heppner, Vladimir Litvak, David M Holtzman, Hans Lassmann, Howard L Weiner, Jordi Ochando, Christian Haass, Oleg Butovsky
Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons...
September 19, 2017: Immunity
https://www.readbyqxmd.com/read/28930654/a-tale-of-two-genes-microglial-apoe-and-trem2
#13
COMMENT
Anna A Pimenova, Edoardo Marcora, Alison M Goate
Microglial cell function is implicated in the etiology of Alzheimer's disease by human genetics. In this issue of Immunity, Krasemann et al. (2017) describe a gene expression signature associated with an APOE- and TREM2-dependent response of microglia to brain tissue damage that accumulates in aging and disease, defining an axis that might be amenable to therapeutic targeting.
September 19, 2017: Immunity
https://www.readbyqxmd.com/read/28677658/abscopal-activation-of-microglia-in-embryonic-fish-brain-following-targeted-irradiation-with-heavy-ion-microbeam
#14
Takako Yasuda, Miyuki Kamahori, Kento Nagata, Tomomi Watanabe-Asaka, Michiyo Suzuki, Tomoo Funayama, Hiroshi Mitani, Shoji Oda
Microglia remove apoptotic cells by phagocytosis when the central nervous system is injured in vertebrates. Ionizing irradiation (IR) induces apoptosis and microglial activation in embryonic midbrain of medaka ( Oryzias latipes ), where apolipoprotein E (ApoE) is upregulated in the later phase of activation of microglia In this study, we found that another microglial marker, l-plastin (lymphocyte cytosolic protein 1), was upregulated at the initial phase of the IR-induced phagocytosis when activated microglia changed their morphology and increased motility to migrate...
July 4, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28578430/expression-profiles-of-cholesterol-metabolism-related-genes-are-altered-during-development-of-experimental-autoimmune-encephalomyelitis-in-the-rat-spinal-cord
#15
Irena Lavrnja, Kosara Smiljanic, Danijela Savic, Aleksandra Mladenovic-Djordjevic, Katarina Tesovic, Selma Kanazir, Sanja Pekovic
Increased evidence suggests that dysregulation of cholesterol metabolism may be a key event contributing to progression of multiple sclerosis (MS). Using an experimental autoimmune encephalomyelitis (EAE) model of MS we revealed specific changes in the mRNA and protein expression of key molecules involved in the maintaining of cholesterol homeostasis in the rat spinal cord: 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR), apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46A1) during the course of disease...
June 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28533891/nuclear-uptake-of-an-amino-terminal-fragment-of-apolipoprotein-e4-promotes-cell-death-and-localizes-within-microglia-of-the-alzheimer-s-disease-brain
#16
Julia E Love, Ryan J Day, Justin W Gause, Raquel J Brown, Xinzhu Pu, Dustin I Theis, Chad A Caraway, Wayne W Poon, Abir A Rahman, Brad E Morrison, Troy T Rohn
Although harboring the apolipoprotein E4 ( APOE4 ) allele is a well known risk factor in Alzheimer's disease (AD), the mechanism by which it contributes to disease risk remains elusive. To investigate the role of proteolysis of apoE4 as a potential mechanism, we designed and characterized a site-directed cleavage antibody directed at position D151 of the mature form of apoE4 and E3. Characterization of this antibody indicated a high specificity for detecting synthesized recombinant proteins corresponding to the amino acid sequences 1-151 of apoE3 and E4 that would generate the 17 kDa (p17) fragment...
2017: International Journal of Physiology, Pathophysiology and Pharmacology
https://www.readbyqxmd.com/read/28434692/immune-hyperreactivity-of-a%C3%AE-plaque-associated-microglia-in-alzheimer-s-disease
#17
Zhuoran Yin, Divya Raj, Nasrin Saiepour, Debby Van Dam, Nieske Brouwer, Inge R Holtman, Bart J L Eggen, Thomas Möller, Joseph A Tamm, Aicha Abdourahman, Elly M Hol, Willem Kamphuis, Thomas A Bayer, Peter P De Deyn, Erik Boddeke
Alzheimer's disease (AD) is strongly associated with microglia-induced neuroinflammation. Particularly, Aβ plaque-associated microglia take on an "activated" morphology. However, the function and phenotype of these Aβ plaque-associated microglia are not well understood. We show hyperreactivity of Aβ plaque-associated microglia upon systemic inflammation in transgenic AD mouse models (i.e., 5XFAD and APP23). Gene expression profiling of Aβ plaque-associated microglia (major histocompatibility complex II+ microglia) isolated from 5XFAD mice revealed a proinflammatory phenotype...
July 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28373057/lysophosphatidylcholine-export-by-human-abca7
#18
Maiko Tomioka, Yoshinobu Toda, Noralyn B Mañucat, Hiroyasu Akatsu, Manabu Fukumoto, Nozomu Kono, Hiroyuki Arai, Noriyuki Kioka, Kazumitsu Ueda
The ATP-binding cassette transporter A7 (ABCA7), which is highly expressed in the brain, is associated with the pathogenesis of Alzheimer's disease (AD). However, the physiological function of ABCA7 and its transport substrates remain unclear. Immunohistochemical analyses of human brain sections from AD and non-AD subjects revealed that ABCA7 is expressed in neuron and microglia cells in the cerebral cortex. The transport substrates and acceptors were identified in BHK/ABCA7 cells and compared with those of ABCA1...
July 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28143566/apoe-genotype-differentially-modulates-effects-of-anti-a%C3%AE-passive-immunization-in-app-transgenic-mice
#19
Joanna E Pankiewicz, Jairo Baquero-Buitrago, Sandrine Sanchez, Jennifer Lopez-Contreras, Jungsu Kim, Patrick M Sullivan, David M Holtzman, Martin J Sadowski
BACKGROUND: APOE genotype is the foremost genetic factor modulating β-amyloid (Aβ) deposition and risk of sporadic Alzheimer's disease (AD). Here we investigated how APOE genotype influences response to anti-Aβ immunotherapy. METHODS: APPSW /PS1dE9 (APP) transgenic mice with targeted replacement of the murine Apoe gene for human APOE alleles received 10D5 anti-Aβ or TY11-15 isotype control antibodies between the ages of 12 and 15 months. RESULTS: Anti-Aβ immunization decreased both the load of fibrillar plaques and the load of Aβ immunopositive plaques in mice of all APOE backgrounds...
January 31, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28106546/a-common-variant-of-il-6r-is-associated-with-elevated-il-6-pathway-activity-in-alzheimer-s-disease-brains
#20
Patrick C G Haddick, Jessica L Larson, Nisha Rathore, Tushar R Bhangale, Qui T Phung, Karpagam Srinivasan, David V Hansen, Jennie R Lill, Margaret A Pericak-Vance, Jonathan Haines, Lindsay A Farrer, John S Kauwe, Gerard D Schellenberg, Carlos Cruchaga, Alison M Goate, Timothy W Behrens, Ryan J Watts, Robert R Graham, Joshua S Kaminker, Marcel van der Brug
The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer's disease subjects in an IL6R allele dependent manner...
2017: Journal of Alzheimer's Disease: JAD
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