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https://www.readbyqxmd.com/read/28306378/development-of-a-monoclonal-anti-adamts-5-antibody-that-specifically-blocks-the-interaction-with-lrp1
#1
Salvatore Santamaria, Oleg Fedorov, John McCafferty, Gillian Murphy, Jayesh Dudhia, Hideaki Nagase, Kazuhiro Yamamoto
The potent aggrecanase ADAMTS-5 is constitutively secreted by chondrocytes, but it is rapidly endocytosed in normal cartilage via the cell surface endocytic receptor LRP1. Therefore it is difficult to detect the total ADAMTS-5 activity produced. In this study, we isolated a monoclonal anti-ADAMTS-5 antibody 1B7 that blocks LRP1-mediated internalization without affecting the aggrecanolytic activity. Addition of 1B7 to cultured human chondrocytes revealed the full aggrecanolytic activity of ADAMTS-5 generated by the cells...
March 17, 2017: MAbs
https://www.readbyqxmd.com/read/28301372/news-on-the-molecular-regulation-and-function-of-hepatic-low-density-lipoprotein-receptor-and-ldlr-related-protein-1
#2
Bart van de Sluis, Melinde Wijers, Joachim Herz
PURPOSE OF REVIEW: Clearing of atherogenic lipoprotein particles by the liver requires hepatic low-density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1). This review highlights recent studies that have expanded our understanding of the molecular regulation and metabolic functions of LDLR and LRP1 in the liver. RECENT FINDINGS: Various proteins orchestrate the intracellular trafficking of LDLR and LRP1. After internalization, the receptors are redirected via recycling endosomes to the cell surface...
March 15, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28275161/astrocytic-lrp1-mediates-brain-a%C3%AE-clearance-and-impacts-amyloid-deposition
#3
Chia-Chen Liu, Jin Hu, Na Zhao, Jian Wang, Wang Na, John R Cirrito, Takahisa Kanekiyo, David M Holtzman, Guojun Bu
Accumulation and deposition of amyloid-β (Aβ) in the brain represents an early and perhaps necessary step in the pathogenesis of Alzheimer's disease (AD). Aβ accumulation leads to the formation of Aβ aggregates which may directly and indirectly lead to eventual neurodegeneration. While Aβ production is accelerated in many familial forms of early-onset AD, increasing evidence indicates that impaired clearance of Aβ is more evident in late-onset AD. To uncover the mechanisms underlying impaired Aβ clearance in AD, we examined the role of low-density lipoprotein receptor-related protein 1 (LRP1) in astrocytes...
March 8, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28263310/deficiency-of-the-hepatokine-selenoprotein-p-increases-responsiveness-to-exercise-in-mice-through-upregulation-of-reactive-oxygen-species-and-amp-activated-protein-kinase-in-muscle
#4
Hirofumi Misu, Hiroaki Takayama, Yoshiro Saito, Yuichiro Mita, Akihiro Kikuchi, Kiyo-Aki Ishii, Keita Chikamoto, Takehiro Kanamori, Natsumi Tajima, Fei Lan, Yumie Takeshita, Masao Honda, Mutsumi Tanaka, Seiji Kato, Naoto Matsuyama, Yuya Yoshioka, Kaito Iwayama, Kumpei Tokuyama, Nobuhiko Akazawa, Seiji Maeda, Kazuhiro Takekoshi, Seiichi Matsugo, Noriko Noguchi, Shuichi Kaneko, Toshinari Takamura
Exercise has numerous health-promoting effects in humans; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly. This 'exercise resistance' is considered to be congenital, with no evident acquired causative factors. Here we show that the anti-oxidative hepatokine selenoprotein P (SeP) causes exercise resistance through its muscle receptor low-density lipoprotein receptor-related protein 1 (LRP1). SeP-deficient mice showed a 'super-endurance' phenotype after exercise training, as well as enhanced reactive oxygen species (ROS) production, AMP-activated protein kinase (AMPK) phosphorylation and peroxisome proliferative activated receptor γ coactivator (Ppargc)-1α (also known as PGC-1α; encoded by Ppargc1a) expression in skeletal muscle...
February 27, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28256585/lrp1-influences-trafficking-of-n-type-calcium-channels-via-interaction-with-the-auxiliary-%C3%AE-2%C3%AE-1-subunit
#5
Ivan Kadurin, Simon W Rothwell, Beatrice Lana, Manuela Nieto-Rostro, Annette C Dolphin
Voltage-gated Ca(2+) (CaV) channels consist of a pore-forming α1 subunit, which determines the main functional and pharmacological attributes of the channel. The CaV1 and CaV2 channels are associated with auxiliary β- and α2δ-subunits. The molecular mechanisms involved in α2δ subunit trafficking, and the effect of α2δ subunits on trafficking calcium channel complexes remain poorly understood. Here we show that α2δ-1 is a ligand for the Low Density Lipoprotein (LDL) Receptor-related Protein-1 (LRP1), a multifunctional receptor which mediates trafficking of cargoes...
March 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28228716/intranasal-bmp9-ameliorates-alzheimer-disease-like-pathology-and-cognitive-deficits-in-app-ps1-transgenic-mice
#6
Zigao Wang, Lu Xiong, Wenbin Wan, Lijie Duan, Xiaojing Bai, Hengbing Zu
Alzheimer's disease (AD) is the most common type of dementia and has no effective therapies. Previous studies showed that bone morphogenetic protein 9 (BMP9), an important factor in the differentiation and phenotype maintenance of cholinergic neurons, ameliorated the cholinergic defects resulting from amyloid deposition. These findings suggest that BMP9 has potential as a therapeutic agent for AD. However, the effects of BMP9 on cognitive function in AD and its underlying mechanisms remain elusive. In the present study, BMP9 was delivered intranasally to 7-month-old APP/PS1 mice for 4 weeks...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28209224/systematic-evaluation-of-pleiotropy-identifies-6-further-loci-associated-with%C3%A2-coronary-artery%C3%A2-disease
#7
Thomas R Webb, Jeanette Erdmann, Kathleen E Stirrups, Nathan O Stitziel, Nicholas G D Masca, Henning Jansen, Stavroula Kanoni, Christopher P Nelson, Paola G Ferrario, Inke R König, John D Eicher, Andrew D Johnson, Stephen E Hamby, Christer Betsholtz, Arno Ruusalepp, Oscar Franzén, Eric E Schadt, Johan L M Björkegren, Peter E Weeke, Paul L Auer, Ursula M Schick, Yingchang Lu, He Zhang, Marie-Pierre Dube, Anuj Goel, Martin Farrall, Gina M Peloso, Hong-Hee Won, Ron Do, Erik van Iperen, Jochen Kruppa, Anubha Mahajan, Robert A Scott, Christina Willenborg, Peter S Braund, Julian C van Capelleveen, Alex S F Doney, Louise A Donnelly, Rosanna Asselta, Pier A Merlini, Stefano Duga, Nicola Marziliano, Josh C Denny, Christian Shaffer, Nour Eddine El-Mokhtari, Andre Franke, Stefanie Heilmann, Christian Hengstenberg, Per Hoffmann, Oddgeir L Holmen, Kristian Hveem, Jan-Håkan Jansson, Karl-Heinz Jöckel, Thorsten Kessler, Jennifer Kriebel, Karl L Laugwitz, Eirini Marouli, Nicola Martinelli, Mark I McCarthy, Natalie R Van Zuydam, Christa Meisinger, Tõnu Esko, Evelin Mihailov, Stefan A Escher, Maris Alver, Susanne Moebus, Andrew D Morris, Jarma Virtamo, Majid Nikpay, Oliviero Olivieri, Sylvie Provost, Alaa AlQarawi, Neil R Robertson, Karen O Akinsansya, Dermot F Reilly, Thomas F Vogt, Wu Yin, Folkert W Asselbergs, Charles Kooperberg, Rebecca D Jackson, Eli Stahl, Martina Müller-Nurasyid, Konstantin Strauch, Tibor V Varga, Melanie Waldenberger, Lingyao Zeng, Rajiv Chowdhury, Veikko Salomaa, Ian Ford, J Wouter Jukema, Philippe Amouyel, Jukka Kontto, Børge G Nordestgaard, Jean Ferrières, Danish Saleheen, Naveed Sattar, Praveen Surendran, Aline Wagner, Robin Young, Joanna M M Howson, Adam S Butterworth, John Danesh, Diego Ardissino, Erwin P Bottinger, Raimund Erbel, Paul W Franks, Domenico Girelli, Alistair S Hall, G Kees Hovingh, Adnan Kastrati, Wolfgang Lieb, Thomas Meitinger, William E Kraus, Svati H Shah, Ruth McPherson, Marju Orho-Melander, Olle Melander, Andres Metspalu, Colin N A Palmer, Annette Peters, Daniel J Rader, Muredach P Reilly, Ruth J F Loos, Alex P Reiner, Dan M Roden, Jean-Claude Tardif, John R Thompson, Nicholas J Wareham, Hugh Watkins, Cristen J Willer, Nilesh J Samani, Heribert Schunkert, Panos Deloukas, Sekar Kathiresan
BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011...
February 21, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/28059785/amylin-enhances-amyloid-%C3%AE-peptide-brain-to-blood-efflux-across-the-blood-brain-barrier
#8
Loqman A Mohamed, Haihao Zhu, Youssef M Mousa, Erming Wang, Wei Qiao Qiu, Amal Kaddoumi
Findings from Alzheimer's disease (AD) mouse models showed that amylin treatment improved AD pathology and enhanced amyloid-β (Aβ) brain to blood clearance; however, the mechanism was not investigated. Using the Tg2576 AD mouse model, a single intraperitoneal injection of amylin significantly increased Aβ serum levels, and the effect was abolished by AC253, an amylin receptor antagonist, suggesting that amylin effect could be mediated by its receptor. Subsequent mechanistic studies showed amylin enhanced Aβ transport across a cell-based model of the blood-brain barrier (BBB), an effect that was abolished when the amylin receptor was inhibited by two amylin antagonists and by siRNA knockdown of amylin receptor Ramp3...
December 3, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28012205/activated-%C3%AE-2-macroglobulin-induces-mesenchymal-cellular-migration-of-raw264-7-cells-through-low-density-lipoprotein-receptor-related-protein-1
#9
Darío G Ferrer, Virginia Actis Dato, Javier R Jaldín Fincati, Valeria E Lorenc, María C Sánchez, Gustavo A Chiabrando
Distinct modes of cell migration contribute to diverse types of cell movements. The mesenchymal mode is characterized by a multistep cycle of membrane protrusion, the formation of focal adhesion, and the stabilization at the leading edge associated with the degradation of extracellular matrix (ECM) components and with regulated extracellular proteolysis. Both α2 -Macroglobulin (α2 M) and its receptor, low density lipoprotein receptor-related protein 1 (LRP1), play important roles in inflammatory processes, by controlling the extracellular activity of several proteases...
December 24, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27986809/urokinase-type-plasminogen-activator-upa-binding-to-the-upa-receptor-upar-promotes-axonal-regeneration-in-the-central-nervous-system
#10
Paola Merino, Ariel Diaz, Valerie Jeanneret, Fang Wu, Enrique Torre, Lihong Cheng, Manuel Yepes
Axonal injury is a common cause of neurological dysfunction. Unfortunately, in contrast to axons from the peripheral nervous system, the limited capacity of regeneration of central nervous system (CNS) axons is a major obstacle for functional recovery in patients suffering neurological diseases that involve the subcortical white matter. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to the urokinase-type plasminogen activator receptor (uPAR) catalyzes the conversion of plasminogen into plasmin on the cell surface...
February 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27979811/high-glucose-facilitated-endothelial-heparanase-transfer-to-the-cardiomyocyte-modifies-its-cell-death-signature
#11
Fulong Wang, Jocelyn Jia, Nathaniel Lal, Dahai Zhang, Amy Pei-Ling Chiu, Andrea Wan, Israel Vlodavsky, Bahira Hussein, Brian Rodrigues
AIMS: The secretion of enzymatically active heparanase (Hep(A)) has been implicated as an essential metabolic adaptation in the heart following diabetes. However, the regulation and function of the enzymatically inactive heparanase (Hep(L)) remain poorly understood. We hypothesized that in response to high glucose (HG) and secretion of Hep(L) from the endothelial cell (EC), Hep(L) uptake and function can protect the cardiomyocyte by modifying its cell death signature. METHODS AND RESULTS: HG promoted both Hep(L) and Hep(A) secretion from microvascular (rat heart micro vessel endothelial cells, RHMEC) and macrovascular (rat aortic endothelial cells, RAOEC) EC...
December 2016: Cardiovascular Research
https://www.readbyqxmd.com/read/27959956/mesenchymal-stromal-cells-promote-axonal-outgrowth-alone-and-synergistically-with-astrocytes-via-tpa
#12
Jian-Yong Qian, Michael Chopp, Zhongwu Liu
We reported that mesenchymal stromal cells (MSCs) enhance neurological recovery from experimental stroke and increase tissue plasminogen activator (tPA) expression in astrocytes. Here, we investigate mechanisms by which tPA mediates MSC enhanced axonal outgrowth. Primary murine neurons and astrocytes were isolated from wild-type (WT) and tPA-knockout (KO) cortices of embryos. Mouse MSCs (WT) were purchased from Cognate Inc. Neurons (WT or KO) were seeded in soma side of Xona microfluidic chambers, and astrocytes (WT or KO) and/or MSCs in axon side...
2016: PloS One
https://www.readbyqxmd.com/read/27956551/recombinant-expression-of-the-full-length-ectodomain-of-ldl-receptor-related-protein-1-lrp1-unravels-ph-dependent-conformational-changes-and-the-stoichiometry-of-binding-with-receptor-associated-protein-rap
#13
Camilla De Nardis, Philip Lössl, Maartje van den Biggelaar, Pramod K Madoori, Nadia Leloup, Koen Mertens, Albert J R Heck, Piet Gros
LDL receptor-related protein 1 (LRP1) is a highly modular protein and the largest known mammalian endocytic receptor. LRP1 binds and internalizes many plasma components, playing multiple crucial roles as a scavenger and signaling molecule. One major challenge to studying LRP1 has been that it is difficult to express such a large, highly glycosylated, and cysteine-rich protein, limiting structural studies to LRP1 fragments. Here, we report the first recombinant expression of the complete 61 domains of the full-length LRP1 ectodomain...
January 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27933291/endocytosis-and-physiology-insights-from-disabled-2-deficient-mice
#14
REVIEW
Wensi Tao, Robert Moore, Elizabeth R Smith, Xiang-Xi Xu
Disabled-2 (Dab2) is a clathrin and cargo binding endocytic adaptor protein, and cell biology studies revealed that Dab2 plays a role in cellular trafficking of a number of transmembrane receptors and signaling proteins. A PTB/PID domain located in the N-terminus of Dab2 binds the NPXY motif(s) present at the cytoplasmic tails of certain transmembrane proteins/receptors. The membrane receptors reported to bind directly to Dab2 include LDL receptor and its family members LRP1 and LRP2 (megalin), growth factor receptors EGFR and FGFR, and the cell adhesion receptor beta1 integrin...
2016: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/27931217/lrp1-modulates-the-microglial-immune-response-via-regulation-of-jnk-and-nf-%C3%AE%C2%BAb-signaling-pathways
#15
Longyu Yang, Chia-Chen Liu, Honghua Zheng, Takahisa Kanekiyo, Yuka Atagi, Lin Jia, Daxin Wang, Aurelie N'songo, Dan Can, Huaxi Xu, Xiao-Fen Chen, Guojun Bu
BACKGROUND: Neuroinflammation is characterized by microglial activation and the increased levels of cytokines and chemokines in the central nervous system (CNS). Recent evidence has implicated both beneficial and toxic roles of microglia when over-activated upon nerve injury or in neurodegenerative diseases, including Alzheimer's disease (AD). The low-density lipoprotein receptor-related protein 1 (LRP1) is a major receptor for apolipoprotein E (apoE) and amyloid-β (Aβ), which play critical roles in AD pathogenesis...
December 8, 2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27924190/network-analysis-of-human-post-mortem-microarrays-reveals-novel-genes-micrornas-and-mechanistic-scenarios-of-potential-importance-in-fighting-huntington-s-disease
#16
Sreedevi Chandrasekaran, Danail Bonchev
Huntington's disease is a progressive neurodegenerative disorder characterized by motor disturbances, cognitive decline, and neuropsychiatric symptoms. In this study, we utilized network-based analysis in an attempt to explore and understand the underlying molecular mechanism and to identify critical molecular players of this disease condition. Using human post-mortem microarrays from three brain regions (cerebellum, frontal cortex and caudate nucleus) we selected in a four-step procedure a seed set of highly modulated genes...
2016: Computational and Structural Biotechnology Journal
https://www.readbyqxmd.com/read/27849881/239-lrp1-an-endocytic-vesicle-trafficking-protein-associated-with-chd-an-unexplored-pathway
#17
Jiuann-Huey Lin, Anupma Jha, Jacob McClreary, Cecilia Lo
No abstract text is available yet for this article.
December 2016: Critical Care Medicine
https://www.readbyqxmd.com/read/27833152/selenium-binding-lactoferrin-is-taken-into-corneal-epithelial-cells-by-a-receptor-and-prevents-corneal-damage-in-dry-eye-model-animals
#18
Akihiro Higuchi, Hiroyoshi Inoue, Yoshio Kaneko, Erina Oonishi, Kazuo Tsubota
The ocular surface is strongly affected by oxidative stress, which causes many ocular diseases including dry eye. Previously, we showed that selenium compounds, e.g., selenoprotein P and Se-lactoferrin, were candidates for treatment of dry eye. This paper shows the efficacy of Se-lactoferrin for the treatment of dry eye compared with Diquas as a control drug using two dry eye models and incorporation of lactoferrin into corneal epithelial cells via lactoferrin receptors. We show the efficacy of Se-lactoferrin eye drops in the tobacco smoke exposure rat dry eye model and short-term rabbit dry eye model, although Diquas eye drops were only effective in the short-term rabbit dry eye model...
November 11, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27829865/improvement-of-electroacupuncture-on-app-ps1-transgenic-mice-in-spatial-learning-and-memory-probably-due-to-expression-of-a%C3%AE-and-lrp1-in-hippocampus
#19
Xin Wang, Yanhuan Miao, Jiawula Abulizi, Fu Li, Yuping Mo, Weiguo Xue, Zhigang Li
Objectives. To explore the alterations of β-amyloid (Aβ) and low density lipoprotein receptor-related protein-1 (LRP1) in APP/PS1 mice after electroacupuncture (EA) treatment and further to explore the mechanism. Methods. Forty 6-month-old APP/PS1 mice were randomly divided into a model group and an EA group, with twenty wild-type mice used as a normal control group. Mice in the EA group were treated with EA at GV 20 (băi huì) and bilateral KI 1 (yŏng quán) acupoints for 6 weeks. The Morris water maze was applied to assess the spatial memory in behavior...
2016: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/27824728/evidence-that-ldl-receptor-related-protein-1-acts-as-an-early-injury-detection-receptor-and-activates-c-jun-in-schwann-cells
#20
Andreas Flütsch, Kenneth Henry, Elisabetta Mantuano, Michael S Lam, Masataka Shibayama, Kazuhisa Takahashi, Steven L Gonias, Wendy M Campana
Schwann cells (SCs) detect injury to peripheral nerves and transform phenotypically to respond to injury and facilitate repair. Cell-signaling pathways and changes in gene expression that drive SC phenotypic transformation in injury have been described; however, the SC receptors that detect peripheral nervous system (PNS) injury have not been identified. LDL receptor-related protein 1 (LRP1) is a receptor for numerous ligands, including intracellular proteins released by injured cells and protein components of degenerated myelin...
December 14, 2016: Neuroreport
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