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https://www.readbyqxmd.com/read/30108311/whole-exome-sequencing-study-identifies-novel-rare-and-common-alzheimer-s-associated-variants-involved-in-immune-response-and-transcriptional-regulation
#1
Joshua C Bis, Xueqiu Jian, Brian W Kunkle, Yuning Chen, Kara L Hamilton-Nelson, William S Bush, William J Salerno, Daniel Lancour, Yiyi Ma, Alan E Renton, Edoardo Marcora, John J Farrell, Yi Zhao, Liming Qu, Shahzad Ahmad, Najaf Amin, Philippe Amouyel, Gary W Beecham, Jennifer E Below, Dominique Campion, Camille Charbonnier, Jaeyoon Chung, Paul K Crane, Carlos Cruchaga, L Adrienne Cupples, Jean-François Dartigues, Stéphanie Debette, Jean-François Deleuze, Lucinda Fulton, Stacey B Gabriel, Emmanuelle Genin, Richard A Gibbs, Alison Goate, Benjamin Grenier-Boley, Namrata Gupta, Jonathan L Haines, Aki S Havulinna, Seppo Helisalmi, Mikko Hiltunen, Daniel P Howrigan, M Arfan Ikram, Jaakko Kaprio, Jan Konrad, Amanda Kuzma, Eric S Lander, Mark Lathrop, Terho Lehtimäki, Honghuang Lin, Kari Mattila, Richard Mayeux, Donna M Muzny, Waleed Nasser, Benjamin Neale, Kwangsik Nho, Gaël Nicolas, Devanshi Patel, Margaret A Pericak-Vance, Markus Perola, Bruce M Psaty, Olivier Quenez, Farid Rajabli, Richard Redon, Christiane Reitz, Anne M Remes, Veikko Salomaa, Chloe Sarnowski, Helena Schmidt, Michael Schmidt, Reinhold Schmidt, Hilkka Soininen, Timothy A Thornton, Giuseppe Tosto, Christophe Tzourio, Sven J van der Lee, Cornelia M van Duijn, Badri Vardarajan, Weixin Wang, Ellen Wijsman, Richard K Wilson, Daniela Witten, Kim C Worley, Xiaoling Zhang, Celine Bellenguez, Jean-Charles Lambert, Mitja I Kurki, Aarno Palotie, Mark Daly, Eric Boerwinkle, Kathryn L Lunetta, Anita L Destefano, Josée Dupuis, Eden R Martin, Gerard D Schellenberg, Sudha Seshadri, Adam C Naj, Myriam Fornage, Lindsay A Farrer
The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants...
August 14, 2018: Molecular Psychiatry
https://www.readbyqxmd.com/read/30101304/immune-system-mediated-atherosclerosis-caused-by-deficiency-of-long-noncoding-rna-malat1-in-apoe-mice
#2
Martina Gast, Bernhard H Rauch, Shinichi Nakagawa, Arash Haghikia, Andrzej Jasina, Jan Haas, Neetika Nath, Lars Jensen, Andrea Stroux, Andreas Böhm, Julian Friebel, Ursula Rauch, Carsten Skurk, Stefan Blankenberg, Tanja Zeller, Kannanganattu V Prasanth, Benjamin Meder, Andreas Kuss, Ulf Landmesser, Wolfgang Poller
Background: The immune system is considered a key driver of atherosclerosis, and beyond proteins and microRNAs (miRs), long noncoding RNAs (lncRNAs) are implicated in immune control. We previously described that lncRNA MALAT1 is involved in cardiac innate immunity in a myocarditis model. Here, we investigated the impact of MALAT1 deficiency upon atherosclerosis development. Methods and Results: Heterozygous MALAT1-deficient ApoE-/- mice displayed massive immune system dysregulation and atherosclerosis within two months even when kept on normal diet...
August 8, 2018: Cardiovascular Research
https://www.readbyqxmd.com/read/30092589/thyroid-hormone-receptor-alpha-deletion-in-apoe-mice-alters-the-arterial-renin-angiotensin-system-and-vascular-smooth-muscular-cell-cholesterol-metabolism
#3
Samia Neggazi, Laurence Canaple, Nadjiba Hamlat, Karine Gauthier, Jacques Samarut, Giampiero Bricca, Souhila Aouichat-Bouguerra, Michel Beylot
Thyroid hormone (TH) regulates gene transcription by binding to TH receptors (TRs). TRs regulate the genes of lipid metabolism and the renin-angiotensin system (RAS). We examined the effect of TRα deletion in ApoE-/- mice (DKO mice) on the following: (i) the expression of genes controlling cholesterol metabolism and tissue (t)RAS in the liver and aorta and (ii) the expression of these genes and the regulation of cholesterol content in cultured vascular smooth muscle cells (VSMCs). TRα deletion in ApoE-/- mice led to the repression of genes involved in the synthesis and influx of cholesterol in the liver...
August 9, 2018: Journal of Vascular Research
https://www.readbyqxmd.com/read/30088830/ho-1-upregulation-by-rosiglitazone-via-ros-dependent-nrf2-are-axis-or-ppar%C3%AE-attenuates-lipopolysaccharide-mediated-lung-inflammation
#4
Rou-Ling Cho, Chien-Chung Yang, Hui-Ching Tseng, Li-Der Hsiao, Chih-Chung Lin, Chuen-Mao Yang
BACKGROUND AND PURPOSE: Heme oxygenase-1 (HO-1) is induced by thiazolidinediones including rosiglitazone and exerts anti-inflammatory effects in various models. However, the molecular mechanisms underlying rosiglitazone-induced HO-1 expression remain largely unknown in human pulmonary alveolar epithelial cells (HPAEpiCs). EXPERIMENTAL APPROACH: HO-1 expression was determined by real time-PCR, western blotting, and promoter reporter analyses. The signaling components were investigated by using pharmacological inhibitors or specific siRNAs...
August 8, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/30082275/microglial-translational-profiling-reveals-a-convergent-apoe-pathway-from-aging-amyloid-and-tau
#5
Silvia S Kang, Mark T W Ebbert, Kelsey E Baker, Casey Cook, Xuewei Wang, Jonathon P Sens, Jeanne-Pierre Kocher, Leonard Petrucelli, John D Fryer
Alzheimer's disease (AD) is an age-associated neurodegenerative disease characterized by amyloidosis, tauopathy, and activation of microglia, the brain resident innate immune cells. We show that a RiboTag translational profiling approach can bypass biases due to cellular enrichment/cell sorting. Using this approach in models of amyloidosis, tauopathy, and aging, we revealed a common set of alterations and identified a central APOE-driven network that converged on CCL3 and CCL4 across all conditions. Notably, aged females demonstrated a significant exacerbation of many of these shared transcripts in this APOE network, revealing a potential mechanism for increased AD susceptibility in females...
August 6, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/30054042/recombinant-leptin-attenuates-abdominal-aortic-aneurysm-formation-in-angiotensin-ii-infused-apolipoprotein-e-deficient-mice
#6
Ying Zhang, Haitao Yuan, Peili Bu, Ying H Shen, Tongbao Liu, Shangming Song, Xiaoyang Hou
Vascular disease can manifest as stenotic plaques or ectatic aneurysms. Human abdominal aortic aneurysms (AAA) comprise an inflammatory disease characterized by the predominance of T helper type 2 (Th2) cytokine expression. Leptin has been clearly demonstrated to play an important role in regulating Th0 cell to Th1. So, we hypothesize that leptin has a protective effect on aneurysm formation. In this study, we demonstrated that intraperitoneal injection of leptin attenuated Ang II-induced AAA formation in ApoE-/- mice with no effect on serum lipids and systolic blood pressure...
July 23, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/30049795/structure-function-analyses-of-the-bacterial-zinc-metalloprotease-effector-protein-gtga-uncovers-key-residues-required-for-deactivating-nf-%C3%AE%C2%BAb
#7
Elliott Jennings, Diego Esposito, Katrin Rittinger, Teresa L M Thurston
The closely related type III secretion system zinc metalloprotease effector proteins GtgA, GogA, and PipA are translocated into host cells during Salmonella infection. They then cleave nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factor subunits, dampening activation of the NF-κB signaling pathway and thereby suppressing host immune responses. We demonstrate here that GtgA, GogA, and PipA cleave a subset of NF-κB subunits including p65, RelB, and cRel but not NF-κB1 and NF-κB2, whereas the functionally similar type III secretion system effector NleC of enteropathogenic and enterohemorrhagic Escherichia coli cleaved all five NF-κB subunits...
July 26, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/30049279/abca1-haplodeficiency-affects-the-brain-transcriptome-following-traumatic-brain-injury-in-mice-expressing-human-apoe-isoforms
#8
Emilie L Castranio, Cody M Wolfe, Kyong Nyon Nam, Florent Letronne, Nicholas F Fitz, Iliya Lefterov, Radosveta Koldamova
Expression of human Apolipoprotein E (APOE) modulates the inflammatory response in an isoform specific manner, with APOE4 isoform eliciting a stronger pro-inflammatory response, suggesting a possible mechanism for worse outcome following traumatic brain injury (TBI). APOE lipidation and stability is modulated by ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein that transports lipids and cholesterol onto APOE. We examined the impact of Abca1 deficiency and APOE isoform expression on the response to TBI using 3-months-old, human APOE3+/+ (E3/Abca1+/+ ) and APOE4+/+ (E4/Abca1+/+ ) targeted replacement mice, and APOE3+/+ and APOE4+/+ mice with only one functional copy of the Abca1 gene (E3/Abca1+/- ; E4/Abca1+/- )...
July 26, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/30015963/associations-of-cxcl16-mir%C3%A2-146a-and-mir%C3%A2-146b-in-atherosclerotic-apolipoprotein-e%C3%A2-knockout-mice
#9
Ai-Jun Ma, Xiao-Yan Zhu, Shao-Nan Yang, Xu-Dong Pan, Ting Wang, Yuan Wang, Xing Xiao, Shi-Hai Liu
Atherosclerosis is the primary cause of cardiovascular and cerebrovascular diseases. Recent studies have revealed that C‑X‑C motif chemokine ligand 16 (CXCL16), microRNA (miR)‑146a and miR‑146b may have important roles in atherosclerotic diseases. However, the associations of CXCL16, miR‑146a and miR‑146b in atherosclerotic diseases in vivo remain unclear. Previous studies have demonstrated that miR‑146a and miR‑146b may negatively regulate the toll like receptor (TLR4)/nuclear factor (NF)‑κB signaling pathway to repress the inflammatory response...
September 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/30014763/chemogenomics-system-pharmacology-mapping-of-potential-drug-targets-for-treatment-of-traumatic-brain-injury
#10
Lirong Wang, Shifan Ma, Ziheng Hu, Terence Francis McGuire, Xiangqun Xie
Traumatic brain injury (TBI) is associated with high mortality and morbidity. Though the death rate of initial trauma has dramatically decreased, no drug has been developed for the secondary injury caused by TBI. TBI appears to be a predisposing risk factor of Alzheimer's disease (AD), while the molecular mechanisms remain unknown. In this study, we have conducted a research investigation of computational chemogenomics system pharmacology (CSP) to identify potential drug targets for TBI treatment. TBI-induced transcriptional profiles were compared with those induced by genetic or chemical perturbations, including TBI drugs in clinical trials...
July 17, 2018: Journal of Neurotrauma
https://www.readbyqxmd.com/read/29991487/pkc%C3%AE-via-activating-transcription-factor-2-mediated-cd36-expression-and-foam-cell-formation-of-ly6c-hi-cells-contributes-to-atherosclerosis
#11
Somasundaram Raghavan, Nikhlesh K Singh, Sivaiah Gali, Arul M Mani, Gadiparthi N Rao
Background -Although the role of thrombin in atherothrombosis is well studied, its role in the pathogenesis of diet-induced atherosclerosis is not known. Methods -Using a mouse model of diet-induced atherosclerosis and molecular biological approaches, here we have explored the role of thrombin and its G protein-coupled receptor (GPCR) signaling in diet-induced atherosclerosis. Results -In exploring the role of GPCR signaling in atherogenesis, we found that thrombin triggers foam cell formation via inducing CD36 expression and these events require Par1-mediated Gα12-Pyk2-Gab1-PKCθ-dependent ATF2 activation...
July 10, 2018: Circulation
https://www.readbyqxmd.com/read/29990559/regulatory-region-single-nucleotide-polymorphisms-of-the-apolipoprotein-e-gene-as-risk-factors-for-alzheimer-s-disease
#12
Jolanta Bratosiewicz-Wasik, Pawel P Liberski, Beata Peplonska, Maria Styczynska, Joanna Smolen-Dzirba, Mariusz Cycon, Tomasz J Wasik
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a complex aetiology. The ε4 allel of the apolipoprotein E gene (APOE) is the only confirmed genetic risk factor for the development of AD. In addition, polymorphisms at the promoter region of the APOE gene are assumed to modulate the susceptibility to AD by their different affinity to the transcription factors thus affecting the expression of the gene. In the presented study, we investigated the association between -491 A/T (rs449647), -427C/T, (rs769446) and -219 T/G (rs405509) single nucleotide polymorphisms (SNPs) of APOE gene and AD risk in the Polish population...
July 7, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29948923/the-transcriptional-regulatory-properties-of-amyloid-beta-1-42-may-include-regulation-of-genes-related-to-neurodegeneration
#13
Duygu Gezen-Ak, İrem L Atasoy, Esin Candaş, Merve Alaylıoğlu, Erdinç Dursun
Our previous study demonstrated the translocation of Aβ1-42 to the nucleus in response to antibiotic treatment, and interpreted it as a possible transcriptional response of Aβ1-42 to antibiotics. The present study aims to investigate how amyloid acts on the key elements of neurodegeneration and the molecules involved in the induction of Aβ1-42 production. For this purpose, we investigated the acute effect of Aβ1-42 on the transcriptional levels of genes that have roles in the mechanisms that produce Aβ itself: alpha secretase (ADAM10), beta secretase (BACE1), the gamma secretase complex (PS-1, PS-2, Nicastrin), the substrate APP, APOE (the significant risk factor for sporadic form of the AD), TREM2 (recently indicated as a contributor to AD risk), NMDAR subunits and PKCzeta (contributors of memory and learning), and key elements of tau pathology such as tau, GSK3α, GSK3β, and Cdk5...
June 12, 2018: Neuromolecular Medicine
https://www.readbyqxmd.com/read/29944822/crystal-structure-of-apo-mef2b-reveals-new-insights-in-dna-binding-and-cofactor-interaction
#14
Xiao Lei, Haoran Shi, Yi Kou, Niroop Rajashekar, Fang Wu, Chandani Sen, Jiang Xu, Lin Chen
The myocyte enhancer factor 2 (MEF2) family of transcription factors plays important roles in developmental processes and adaptive responses. Although MEF2 proteins are known to bind DNA in the nucleus to regulate specific gene expression, there are reports that show that MEF2 also functions in the cytoplasm. Previous structural studies of MEF2 focused exclusively on DNA-bound MEF2 with and without various corepressors or coactivators. While these studies have established a comprehensive structural model of DNA recognition and cofactor recruitment by MEF2, the structure of MEF2 not bound to DNA, which include cytoplasmic MEF2 and free MEF2 in the nucleus, is unknown...
July 17, 2018: Biochemistry
https://www.readbyqxmd.com/read/29943223/inhibition-of-endoplasmic-reticulum-stress-by-intermedin1-53-attenuates-angiotensin-ii-induced-abdominal-aortic-aneurysm-in-apoe-ko-mice
#15
Xian-Qiang Ni, Wei-Wei Lu, Jin-Sheng Zhang, Qing Zhu, Jin-Ling Ren, Yan-Rong Yu, Xiu-Ying Liu, Xiu-Jie Wang, Mei Han, Qing Jing, Jie Du, Chao-Shu Tang, Yong-Fen Qi
Endoplasmic reticulum stress (ERS) is involved in the development of abdominal aortic aneurysm (AAA). Since bioactive peptide intermedin (IMD)1-53 protects against AAA formation, here we investigated whether IMD1-53 attenuates AAA by inhibiting ERS. AAA model was induced by angiotensin II (AngII) in ApoE KO mouse background. AngII-treated mouse aortas showed increased ERS gene transcription of caspase12, eukaryotic translation initiation factor 2a (eIf2a) and activating transcription factor 4(ATF4).The protein level of ERS marker glucose regulated protein 94(GRP94), ATF4 and C/EBP homologous protein 10(CHOP) was also up-regulated by AngII...
June 26, 2018: Endocrine
https://www.readbyqxmd.com/read/29920371/cysteinyl-leukotriene-pathway-as-a-new-therapeutic-target-for-the-treatment-of-atherosclerosis-related-to-obstructive-sleep-apnea-syndrome
#16
Elodie Gautier-Veyret, Magnus Bäck, Claire Arnaud, Elise Belaïdi, Renaud Tamisier, Patrick Lévy, Nathalie Arnol, Marion Perrin, Jean-Louis Pépin, Françoise Stanke-Labesque
AIMS: Obstructive sleep apnea (OSA) characterized by nocturnal intermittent hypoxia (IH) is associated with atherosclerosis and cysteinyl-leukotrienes (CysLT) pathway activation. We aimed to identify the determinants of CysLT pathway activation and the role of CysLT in OSA-related atherosclerosis. METHODS AND RESULTS: Determinants of the urinary excretion of LTE4 (U-LTE4 ) including history of cardiovascular events, polysomnographic and biological parameters were studied in a cohort of 170 OSA patients and 29 controls, and in a subgroup of OSA patients free of cardiovascular event (n = 136)...
August 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29917052/nrf2-deficiency-impairs-atherosclerotic-lesion-development-but-promotes-features-of-plaque-instability-in-hypercholesterolemic-mice
#17
Anna-Kaisa Ruotsalainen, Jari P Lappalainen, Emmi Heiskanen, Mari Merentie, Virve Sihvola, Juha Näpänkangas, Line Lottonen-Raikaslehto, Emilia Kansanen, Simone Adinolfi, Kai Kaarniranta, Seppo Ylä-Herttuala, Matti Jauhiainen, Eija Pirinen, Anna-Liisa Levonen
Aims: Oxidative stress and inflammation play an important role in the progression of atherosclerosis. Transcription factor NF-E2-related factor 2 (Nrf2) has antioxidant and anti-inflammatory effects in the vessel wall, but paradoxically, global loss of Nrf2 in apoE deficient mice alleviates atherosclerosis. In this study, we investigated the effect of global Nrf2 deficiency on early and advanced atherogenesis in alternative models of atherosclerosis, LDL receptor deficient mice (LDLR-/-) and LDLR-/- mice expressing apoB-100 only (LDLR-/-ApoB100/100) having a humanized lipoprotein profile...
June 18, 2018: Cardiovascular Research
https://www.readbyqxmd.com/read/29906534/anti-inflammatory-effect-of-low-molecular-weight-fucoidan-from-saccharina-japonica-on-atherosclerosis-in-apoe-knockout-mice
#18
Yingjie Xu, Jie Xu, Keli Ge, Qingwu Tian, Peng Zhao, Yunliang Guo
Atherosclerosis (AS) is the key cause of many cardiovascular and cerebrovascular diseases. The inflammatory response and lipid metabolism disorders contribute to the development and progression of AS. This work aims to study the anti-inflammatory effect and mechanism of low molecular weight fucoidan (LMWF) obtained from Saccharina japonica on atherosclerosis in apoE-knockout mice. The experimental results showed that LMWF statistically decreased the levels of triglyceride (TRIG) and oxidative low-density lipoproteins (ox-LDL) and stabilized established atherosclerotic lesions...
June 12, 2018: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29880855/modular-ssdna-binding-and-inhibition-of-telomerase-activity-by-designer-ppr-proteins
#19
Henrik Spåhr, Tiongsun Chia, James P Lingford, Stefan J Siira, Scott B Cohen, Aleksandra Filipovska, Oliver Rackham
DNA is typically found as a double helix, however it must be separated into single strands during all phases of DNA metabolism; including transcription, replication, recombination and repair. Although recent breakthroughs have enabled the design of modular RNA- and double-stranded DNA-binding proteins, there are currently no tools available to manipulate single-stranded DNA (ssDNA). Here we show that artificial pentatricopeptide repeat (PPR) proteins can be programmed for sequence-specific ssDNA binding. Interactions occur using the same code and specificity as for RNA binding...
June 7, 2018: Nature Communications
https://www.readbyqxmd.com/read/29874096/cholesterol-unbound-ror%C3%AE-t-protein-enables-a-sensitive-inverse-agonist-screening
#20
Ryokichi Koyama, Yasunori Fukuda, Yusuke Kamada, Hideyuki Nakagawa, Darbi Witmer, Geza Ambrus-Aikelin, Bi-Ching Sang, Masaharu Nakayama, Hidehisa Iwata
The retinoic acid-related orphan receptor gamma T (RORγt) plays an important role in Th17 cell proliferation and functionality. Thus, RORγt inverse agonists are thought to be potent therapeutic agents for Th17-mediated autoimmune diseases, such as rheumatoid arthritis, asthma, inflammatory bowel disease, and psoriasis. Although RORγt has constitutive activity, it is recognized that the receptor is physiologically regulated by various cholesterol derivatives. In this study, we sought to identify RORγt inverse agonists through a high-throughput screening campaign...
May 2018: Assay and Drug Development Technologies
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