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Apoe knockout microglia

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
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
Jianjun Zhong, Chongjie Cheng, Han Liu, Zhijian Huang, Yue Wu, Zhipeng Teng, Junchi He, Hongrong Zhang, Jinchuan Wu, Fang Cao, Li Jiang, Xiaochuan Sun
Bexarotene has been proved to have neuroprotective effects in many animal models of neurological diseases. However, its neuroprotection in traumatic brain injury (TBI) is still unknown. This study aims to explore the neuroprotective effects of bexarotene on TBI and its possible mechanism. Controlled cortical impact (CCI) model was used to simulate TBI in C57BL/6 mice as well as APOE gene knockout (APOE-KO) mice. After CCI, mice were daily dosed with bexarotene or vehicle solution intraperitoneally. The motor function, learning and memory, inflammatory factors, microglia amount, apoptosis condition around injury site and main side-effects were all measured...
February 20, 2017: Neuroscience
Yimei Liu, Xiaohua Xu, Hongbo Dou, Ying Hua, Jinwen Xu, Xu Hui
More and more evidences suggestted that ApoE plays an important role in modulating the systemic and central nervous inflammatory responses. However, there is a lack of exacted mechanism of ApoE. In this study, we aimed to investigate whether apolipoprotein E (ApoE) induced inflammatory responses and apoptosis in neonatal mice brain from ApoE deficient (ApoE(-/-)) and wildtype (WT). Compared to control group, the microglia cell from ApoE(-/-) mice showed more severe inflammation and cell death such as iNOS and IL-1β...
2015: International Journal of Clinical and Experimental Medicine
Xianwu Li, Kathleen S Montine, C Dirk Keene, Thomas J Montine
Several lines of evidence support immune response in brain as a mechanism of injury in Alzheimer disease (AD). Moreover, immune activation is heightened in apolipoprotein E (APOE) ε4 carriers; inhibitors of prostaglandin (PG) synthesis show a partially protective effect on AD risk from APOE ε4; and genetic variants in triggering receptor expressed on myeloid cells 2 (TREM2) are a rare but potent risk for AD. We tested the hypothesis that APOE ε4 inheritance modulates both the PGE2 pathway and TREM2 expression using primary murine microglia from targeted replacement (TR) APOE3/3 and APOE4/4 mice...
May 2015: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Sophie Stukas, Jerome Robert, Michael Lee, Iva Kulic, Michael Carr, Katherine Tourigny, Jianjia Fan, Dhananjay Namjoshi, Kalistyne Lemke, Nicole DeValle, Jeniffer Chan, Tammy Wilson, Anna Wilkinson, Rafi Chapanian, Jayachandran N Kizhakkedathu, John R Cirrito, Michael N Oda, Cheryl L Wellington
BACKGROUND: Brain lipoprotein metabolism is dependent on lipoprotein particles that resemble plasma high-density lipoproteins but that contain apolipoprotein (apo) E rather than apoA-I as their primary protein component. Astrocytes and microglia secrete apoE but not apoA-I; however, apoA-I is detectable in both cerebrospinal fluid and brain tissue lysates. The route by which plasma apoA-I enters the central nervous system is unknown. METHODS AND RESULTS: Steady-state levels of murine apoA-I in cerebrospinal fluid and interstitial fluid are 0...
December 2014: Journal of the American Heart Association
Ji Hyun Kim, Ki Whan Hong, Sun Sik Bae, Yong-Il Shin, Byung Tae Choi, Hwa Kyoung Shin
Probucol, a lipid-lowering agent with anti-oxidant properties, is involved in protection against atherosclerosis, while cilostazol, an antiplatelet agent, has diverse neuroprotective properties. In this study, we investigated the anti-inflammatory effects of probucol and cilostazol on focal cerebral ischemia with hypercholesterolemia. Apolipoprotein E (ApoE) knockout (KO) mice were fed a high-fat diet (HFD) with or without 0.3% probucol and/or 0.2% cilostazol for 10 weeks. To assess the protective effects of the combined therapy of probucol and cilostazol on ischemic injury, the mice received 40 min of middle cerebral artery occlusion (MCAO)...
September 2014: International Journal of Molecular Medicine
Xin Yan, Fan Yang, Jan Lukas, Martin Witt, Andreas Wree, Arndt Rolfs, Jiankai Luo
Niemann-Pick disease type C1 (NPC1) is a neurodegenerative disease with various progressive pathological features, for example, neuronal loss, dysmyelination, abnormal axon swelling, and gliosis, in the brain. Pathological activation of p38-mitogen-activated protein kinase (MAPK) results in hyperphosphorylation of tau protein, which contributes to the development of neurodegenerative diseases. In this study, axonal varicosities or spheroids and presynaptic aggregates in the spinal cord of the Npc1 mutant mice were found from postnatal day (P) 35 onwards, as indicated by the increased hyperphosphorylated neurofilament and synaptophysin immunoreactivity as well as the findings from electron microscopy...
July 2014: Glia
Joanna M Karasinska, Willeke de Haan, Sonia Franciosi, Piers Ruddle, Jianjia Fan, Janine K Kruit, Sophie Stukas, Dieter Lütjohann, David H Gutmann, Cheryl L Wellington, Michael R Hayden
ATP-binding cassette transporter A1 (ABCA1) mediates cellular cholesterol efflux in the brain and influences whole brain cholesterol homeostasis. Activation of liver X receptors (LXRs), transcription factors that increase the expression of cholesterol transport genes including ABCA1, reduces neuroinflammation and pathology in neurodegenerative animal models suggesting that in addition to its involvement in cholesterol transport, ABCA1 may play a role in modulating the inflammatory response in the brain. We investigated the cell-type specific role of ABCA1 in neuroinflammation in vivo using mice specifically lacking brain ABCA1 (ABCA1(-B/-B)) as well as mice lacking neuronal (ABCA1(-N/-N)) and astrocytic (ABCA1(-Ast/-Ast)) ABCA1...
June 2013: Neurobiology of Disease
C Y Daniel Lee, Wayne Tse, Jonathan D Smith, Gary E Landreth
Allelic variation in the apolipoprotein E (APOE) gene is the major risk factor of sporadic Alzheimer disease. ApoE is the primary cholesterol carrier in the brain. Previously, we demonstrated that intracellular degradation of β-amyloid (Aβ) peptides by microglia is dramatically enhanced in the presence of apoE. However, the molecular mechanisms subserving this effect remain unknown. This study reports a mechanistic link between apoE-regulated cholesterol homeostasis and Aβ degradation. We demonstrate that promoting intracellular Aβ degradation by microglia is a common feature of HDL apolipoproteins, including apoE and apoA-I...
January 13, 2012: Journal of Biological Chemistry
Sophie Stukas, Sharon May, Anna Wilkinson, Jeniffer Chan, James Donkin, Cheryl L Wellington
Lipoprotein metabolism in the central nervous system (CNS) is based on high-density lipoprotein-like particles that use apoE as their predominant apolipoprotein rather than apoA-I. Although apoA-I is not expressed in astrocytes and microglia, which produce CNS apoE, apoA-I is reported to be expressed in porcine brain capillary endothelial cells and also crosses the blood-brain barrier (BBB). These mechanisms allow apoA-I to reach concentrations in cerebrospinal fluid (CSF) that are approximately 0.5% of its plasma levels...
March 2012: Biochimica et Biophysica Acta
Eiron Cudaback, Xianwu Li, Kathleen S Montine, Thomas J Montine, C Dirk Keene
Complement component C5a and ATP are potent effectors of microglial movement and are increased in diverse neurodegenerative diseases and at sites of injury. Apolipoprotein E (apoE) influences microglial function, and different human apoE isoforms confer variable risk for development of neurodegenerative disorders, especially Alzheimer's disease. The purpose of this investigation was to test the hypothesis that mouse apoE and human apoE isoforms influence microglial migration. Using primary wild-type and apoE-deficient microglia, we show that C5a- and ATP-stimulated chemotaxis are largely apoE-dependent processes with different molecular bases...
June 2011: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Caroline Drake, Hervé Boutin, Matthew S Jones, Adam Denes, Barry W McColl, Johann R Selvarajah, Sharon Hulme, Rachel F Georgiou, Rainer Hinz, Alexander Gerhard, Andy Vail, Christian Prenant, Peter Julyan, Renaud Maroy, Gavin Brown, Alison Smigova, Karl Herholz, Michael Kassiou, David Crossman, Sheila Francis, Spencer D Proctor, James C Russell, Stephen J Hopkins, Pippa J Tyrrell, Nancy J Rothwell, Stuart M Allan
Chronic systemic inflammatory conditions, such as atherosclerosis, diabetes and obesity are associated with increased risk of stroke, which suggests that systemic inflammation may contribute to the development of stroke in humans. The hypothesis that systemic inflammation may induce brain pathology can be tested in animals, and this was the key objective of the present study. First, we assessed inflammatory changes in the brain in rodent models of chronic, systemic inflammation. PET imaging revealed increased microglia activation in the brain of JCR-LA (corpulent) rats, which develop atherosclerosis and obesity, compared to the control lean strain...
August 2011: Brain, Behavior, and Immunity
D Famer, L-O Wahlund, M Crisby
We have previously shown that a high cholesterol (HC) diet results in increases in microglia load and levels of the pro-inflammatory cytokine interleukin-6 (IL-6) in the brains of wild type (WT) and apolipoprotein E knockout (ApoE-/-) mice. In the present investigation, we analyzed whether treatment with rosuvastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, would prevent the increases in inflammatory microglia and IL-6 levels in the brain and plasma of WT and ApoE-/- mice...
November 12, 2010: Biochemical and Biophysical Research Communications
Shu-Lin Liu, Yi-Heng Li, Guey-Yueh Shi, Sei-Hui Tang, Shinn-Jong Jiang, Chia-Wei Huang, Ping-Yen Liu, Jau-Shyong Hong, Hua-Lin Wu
AIMS: Macrophage-related oxidative stress plays an important role in the inflammatory process in atherosclerosis. Recently, dextromethorphan (DXM), a common cough-suppressing ingredient with a high safety profile, was found to inhibit the activation of microglia, the resident macrophage in the nervous system. We investigated whether DXM could reduce macrophage production of cytokines and superoxide and the resultant influence on atherosclerosis formation in mice. METHODS AND RESULTS: We used in vitro and in vivo studies to evaluate the DXM inhibitory effect on oxidative stress...
April 1, 2009: Cardiovascular Research
Michael P Vitek, Candice M Brown, Carol A Colton
Apolipoprotein-E protein is an endogenous immunomodulatory agent that affects both the innate and the adaptive immune responses. Since individuals with the APOE4 gene demonstrate worsened pathology and poorer outcomes in many neurological disorders, we examined isoform-specific differences in the response of microglia, the primary cellular component of the brain's innate immune response, in detail. Our data demonstrate that microglia derived from APOE4/4 targeted replacement mice demonstrate a pro-inflammatory phenotype that includes altered cell morphology, increased NO production associated with increased NOS2 mRNA levels, and higher pro-inflammatory cytokine production (TNFalpha, IL-6, IL12p40) compared to microglia derived from APOE3/3 targeted replacement mice...
September 2009: Neurobiology of Aging
Iliya Lefterov, Angie Bookout, Zhu Wang, Matthias Staufenbiel, David Mangelsdorf, Radosveta Koldamova
BACKGROUND: Recent studies demonstrate that in addition to its modulatory effect on APP processing, in vivo application of Liver X Receptor agonist T0901317 (T0) to APP transgenic and non-transgenic mice decreases the level of Abeta42. Moreover, in young Tg2576 mice T0 completely reversed contextual memory deficits. Compared to other tissues, the regulatory functions of LXRs in brain remain largely unexplored and our knowledge so far is limited to the cholesterol transporters and apoE...
October 22, 2007: Molecular Neurodegeneration
Shu-Lin Liu, Yi-Heng Li, Guey-Yueh Shi, Yung-Huan Chen, Chia-Wei Huang, Jau-Shyong Hong, Hua-Lin Wu
OBJECTIVES: We investigated whether naloxone could reduce macrophage activation and influence atherosclerotic lesion formation in mice. BACKGROUND: Macrophages play an important role in the inflammatory process in atherosclerosis. Naloxone could inhibit activation of microglia, the resident macrophage in the nervous system. METHODS: The anti-inflammatory effect of naloxone was evaluated by stimulating the macrophage cell culture and FVB mice with lipopolysaccharide or oxidized low-density lipoprotein with and without naloxone pretreatment...
November 7, 2006: Journal of the American College of Cardiology
Rui-Sheng Duan, Zhiguo Chen, Ying-Chun Dou, Hernan Concha Quezada, Inger Nennesmo, Abdu Adem, Bengt Winblad, Jie Zhu
Apolipoprotein E (apoE) down-regulates microglial activation and the secretion of inflammatory molecules in an isoform specific fashion (E2 > E3 > E4); the E4 isoform is over-represented in Alzheimer cases while E2 is under-represented. To better define the role of apoE in neurodegeneration, we contrasted apoE knockout (n = 38) and wild-type mice (n = 41) with respect to seizure activity, mortality, locomotion, hippocampal microglial activation/chemokine receptor expression, and damage to the hippocampus after nasal administration of kainic acid (KA) (water as controls)...
December 2006: Experimental Neurology
Si Qin, Catherine Colin, Ina Hinners, Annie Gervais, Cyril Cheret, Michel Mallat
Because senile plaques in Alzheimer's disease (AD) contain reactive microglia in addition to potentially neurotoxic aggregates of amyloid-beta (Abeta), we examined the influence of microglia on the viability of rodent neurons in culture exposed to aggregated Abeta 1-40. Microglia enhanced the toxicity of Abeta by releasing glutamate through the cystine-glutamate antiporter system Xc-. This may be relevant to Abeta toxicity in AD, because the system Xc(-)-specific xCT gene is expressed not only in cultured microglia but also in reactive microglia within or surrounding amyloid plaques in transgenic mice expressing mutant human amyloid precursor protein or in wild-type mice injected with Abeta...
March 22, 2006: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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