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151. Cytokines interleukin-1beta and tumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells.

Author

Ortis F, Naamane N, Flamez D, Ladrière L, Moore F, Cunha DA, Colli ML, Thykjaer T, Thorsen K, Orntoft TF, Eizirik DL, Ortis, Fernanda, Naamane, Najib, Flamez, Daisy, Ladrière, Laurence, Moore, Fabrice, Cunha, Daniel A, Colli, Maikel L, Thykjaer, Thomas, and Thorsen, Kasper

Abstract

Objective: Cytokines contribute to pancreatic beta-cell death in type 1 diabetes. This effect is mediated by complex gene networks that remain to be characterized. We presently utilized array analysis to define the global expression pattern of genes, including spliced variants, modified by the cytokines interleukin (IL)-1beta + interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha + IFN-gamma in primary rat beta-cells.Research Design and Methods: Fluorescence-activated cell sorter-purified rat beta-cells were exposed to IL-1beta + IFN-gamma or TNF-alpha + IFN-gamma for 6 or 24 h, and global gene expression was analyzed by microarray. Key results were confirmed by RT-PCR, and small-interfering RNAs were used to investigate the mechanistic role of novel and relevant transcription factors identified by pathway analysis. RESULTS Nearly 16,000 transcripts were detected as present in beta-cells, with temporal differences in the number of genes modulated by IL-1beta + IFNgamma or TNF-alpha + IFN-gamma. These cytokine combinations induced differential expression of inflammatory response genes, which is related to differential induction of IFN regulatory factor-7. Both treatments decreased the expression of genes involved in the maintenance of beta-cell phenotype and growth/regeneration. Cytokines induced hypoxia-inducible factor-alpha, which in this context has a proapoptotic role. Cytokines also modified the expression of >20 genes involved in RNA splicing, and exon array analysis showed cytokine-induced changes in alternative splicing of >50% of the cytokine-modified genes.Conclusions: The present study doubles the number of known genes expressed in primary beta-cells, modified or not by cytokines, and indicates the biological role for several novel cytokine-modified pathways in beta-cells. It also shows that cytokines modify alternative splicing in beta-cells, opening a new avenue of research for the field. [ABSTRACT FROM AUTHOR]

Published
2010
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152. Use of a systems biology approach to understand pancreatic beta-cell death in Type 1 diabetes.

Author

Eizirik, Decio L., Moore, Fabrice, Flamez, Daisy, Ortis, Fernanda, Eizirik, Decio L., Moore, Fabrice, Flamez, Daisy, and Ortis, Fernanda

Abstract

Accumulating evidence indicates that beta-cells die by apoptosis in T1DM (Type 1 diabetes mellitus). Apoptosis is an active gene-directed process, and recent observations suggest that beta-cell apoptosis depends on the parallel and/or sequential up- and down-regulation of hundreds of genes controlled by key transcription factors such as NF-kappaB (nuclear factor kappaB) and STAT-1 (signal transducer and activator of transcription 1). Understanding the regulation of these gene networks, and how they modulate beta-cell death and the 'dialogue' between beta-cells and the immune system, will require a systems biology approach to the problem. This will hopefully allow the search for a cure for T1DM to move from a 'trial-and-error' approach to one that is really mechanistically driven., Journal Article, Research Support, Non-U.S. Gov't, Review, info:eu-repo/semantics/published

Published
2008

153. Double-stranded RNA induces pancreatic beta-cell apoptosis by activation of the toll-like receptor 3 and interferon regulatory factor 3 pathways.

Author

Dogusan, Zeynep, García, Mónica, Flamez, Daisy, Alexopoulou, Lena, Goldman, Michel, Gysemans, Conny, Mathieu, Chantal, Libert, Claude, Eizirik, Decio L., Rasschaert, Joanne, Dogusan, Zeynep, García, Mónica, Flamez, Daisy, Alexopoulou, Lena, Goldman, Michel, Gysemans, Conny, Mathieu, Chantal, Libert, Claude, Eizirik, Decio L., and Rasschaert, Joanne

Abstract

OBJECTIVE: Viral infections contribute to the pathogenesis of type 1 diabetes. Viruses, or viral products such as double-stranded RNA (dsRNA), affect pancreatic beta-cell survival and trigger autoimmunity by unknown mechanisms. We presently investigated the mediators and downstream effectors of dsRNA-induced beta-cell death. RESEARCH DESIGN AND METHODS: Primary rat beta-cells and islet cells from wild-type, toll-like receptor (TLR) 3, type I interferon receptor (IFNAR1), or interferon regulatory factor (IRF)-3 knockout mice were exposed to external dsRNA (external polyinosinic-polycytidylic acid [PICex]) or were transfected with dsRNA ([PICin]). RESULTS: TLR3 signaling mediated PICex-induced nuclear factor-kappaB (NF-kappaB) and IRF-3 activation and beta-cell apoptosis. PICin activated NF-kappaB and IRF-3 in a TLR3-independent manner, induced eukaryotic initiation factor 2 alpha phosphorylation, and triggered a massive production of interferon (IFN)-beta. This contributed to beta-cell death, as islet cells from IFNAR1(-/-) or IRF-3(-/-) mice were protected against PICin-induced apoptosis. CONCLUSIONS: PICex and PICin trigger beta-cell apoptosis via the TLR3 pathway or IRF-3 signaling, respectively. Execution of PICin-mediated apoptosis depends on autocrine effects of type I IFNs., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2008

154. Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor -/- mice

Author

Raymond A. Pederson, Daisy Flamez, Daniel J. Drucker, Michael B. Wheeler, Malathy Satkunarajah, Louise A. Scrocchi, Frans Schuit, and Christopher H.S. McIntosh

Subjects
Blood Glucose, endocrine system, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Gastric Inhibitory Polypeptide, Biology, Glucagon, Glucagon-Like Peptide-1 Receptor, Islets of Langerhans, Mice, Gastric inhibitory polypeptide, Internal medicine, Insulin Secretion, Internal Medicine, medicine, Receptors, Glucagon, Animals, Insulin, RNA, Messenger, Pancreas, Pancreatic hormone, Proinsulin, Glucose tolerance test, medicine.diagnostic_test, digestive, oral, and skin physiology, Glucose Tolerance Test, Pancreatic Hormones, Glucagon-like peptide-1, Mice, Mutant Strains, Endocrinology, Gastrointestinal hormone, hormones, hormone substitutes, and hormone antagonists
Abstract

Incretins are gastrointestinal hormones that act on the pancreas to potentiate glucose-stimulated insulin secretion. Despite the physiological importance of the enteroinsular axis, disruption of glucagon-like peptide (GLP)-1 action is associated with only modest glucose intolerance in GLP-1 receptor -/- (GLP-1R -/-) mice. We show here that GLP-1R -/- mice exhibit compensatory changes in the enteroinsular axis via increased glucose-dependent insulinotropic polypeptide (GIP) secretion and enhanced GIP action. Serum GIP levels in GLP-1R -/- mice were significantly elevated versus those in +/+ control mice after an oral glucose tolerance test (369 +/- 40 vs. 236 +/- 28 pmol/l; P < or = 0.02). Furthermore, GIP perfusion of mice pancreas and isolated islets in the presence of elevated glucose concentrations elicited a significantly greater insulin response in GLP-1R -/- than in +/+ mice (P < or = 0.02-0.05). In contrast, no significant perturbation in the insulin response to perfused glucagon was detected under conditions of low (4.4 mmol/l) or high (16.6 mmol/l) glucose in GLP-1R -/- mice. Total pancreatic insulin but not glucagon content was significantly reduced in GLP-1R -/- compared with in +/+ mice (77 +/- 9 vs. 121 +/- 10 pmol/mg protein; P < or = 0.005). These observations suggest that upregulation of the GIP component of the enteroinsular axis, at the levels of GIP secretion and action, modifies the phenotype resulting from interruption of the insulinotropic activity of GLP-1 in vivo.

Published
1998

155. Mouse pancreatic beta-cells exhibit preserved glucose competence after disruption of the glucagon-like peptide-1 receptor gene

Author

A Van Breusegem, Louise A. Scrocchi, Daniel Pipeleers, Daniel J. Drucker, Erik Quartier, Frans Schuit, and Daisy Flamez

Subjects
Male, endocrine system, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Incretin, Biology, In Vitro Techniques, Glucagon, Glucagon-Like Peptide-1 Receptor, Islets of Langerhans, Mice, Glucagon-Like Peptide 1, Internal medicine, Insulin Secretion, Internal Medicine, medicine, Receptors, Glucagon, Animals, Insulin, RNA, Messenger, Protein Precursors, Receptor, Pancreatic hormone, Pancreatic islets, digestive, oral, and skin physiology, Glucagon-like peptide-1, Peptide Fragments, Insulin oscillation, Endocrinology, medicine.anatomical_structure, Glucose, Organ Specificity, Female, hormones, hormone substitutes, and hormone antagonists
Abstract

Previous work suggested that glucagon-like peptide 1 (GLP-1) can acutely regulate insulin secretion in two ways, 1) by acting as an incretin, causing amplification of glucose-induced insulin release when glucose is given orally as opposed to intravenous glucose injection; and 2) by keeping the beta-cell population in a glucose-competent state. The observation that mice with homozygous disruption of the GLP-1 receptor gene are diabetic with a diminished incretin response to glucose underlines the first function in vivo. Isolated islets of Langerhans from GLP-1 receptor -/- mice were studied to assess the second function in vitro. Absence of pancreatic GLP-1 receptor function was observed in GLP-1 receptor -/- mice, as exemplified by loss of [125I]GLP-1 binding to pancreatic islets in situ and by the lack of GLP-1 potentiation of glucose-induced insulin secretion from perifused islets. Acute glucose competence of the beta-cells, assessed by perifusing islets with stepwise increases of the medium glucose concentration, was well preserved in GLP-1 receptor -/- islets in terms of insulin secretion. Furthermore, neither islet nor total pancreatic insulin content was significantly changed in the GLP-1 receptor -/- mice when compared with age-and sex-matched controls. In conclusion, mouse islets exhibit preserved insulin storage capacity and glucose-dependent insulin secretion despite the loss of functional GLP-1 receptors. The results demonstrate that the glucose responsiveness of islet beta-cells is well preserved in the absence of GLP-1 receptor signaling.

Published
1998

156. Dual glucagon recognition by pancreatic beta-cells via glucagon and glucagon-like peptide 1 receptors

Author

C. Van Schravendijk, Frans Schuit, Zhidong Ling, Daisy Flamez, Karen Moens, Daniel Pipeleers, Medical Biochemistry, and Pathologic Biochemistry and Physiology

Subjects
Male, medicine.medical_specialty, endocrine system, Endocrinology, Diabetes and Metabolism, Glucagon-Like Peptides, Incretin, Glucagon binding, Biology, Glucagon, Glucagon-Like Peptide-1 Receptor, Iodine Radioisotopes, Rats, Sprague-Dawley, Islets of Langerhans, Glucagon-Like Peptide 1, Internal medicine, medicine, Internal Medicine, Cyclic AMP, Receptors, Glucagon, Animals, Insulin, Glucagon-like peptide 1 receptor, Pancreatic hormone, Cells, Cultured, digestive, oral, and skin physiology, Peptide Fragments, Rats, beta cells, Endocrinology, Liver, glucagon, Glucagon receptor family, Glucagon receptor, hormones, hormone substitutes, and hormone antagonists
Abstract

cAMP is required for normal glucose-induced insulin release by pancreatic beta-cells. In a previous study, we showed that cAMP production in beta-cells depends on the expression of receptors for glucagon, glucagon-like peptide 1(7-36) amide [GLP-1(7-36) amide], and glucose-dependent insulinotropic polypeptide. Although the latter two peptides are thought to amplify meal-induced insulin release (incretin effect), the role of glucagon in the regulation of insulin release remains elusive. In the present study, we analyzed the interaction of glucagon with its own receptor and with the glucagon-like peptide 1 (GLP-1) receptor using purified rat beta-cells. Glucagon binding was partially displaced by 1 micromol/l des-His1-[Glu9]glucagon-amide, a glucagon receptor antagonist, and by 1 micromol/l GLP-1. Conversely, GLP-1 binding was competitively inhibited by high glucagon concentrations (Ki = 0.3 micromol/l). Glucagon-induced cAMP production in beta-cells was inhibited both by 1 micromol/l des-His1-[Glu9]glucagon-amide and exendin-(9-39)-amide, a specific GLP-1 receptor antagonist, whereas GLP-1-induced cAMP formation was suppressed only by exendin-(9-39)-amide. Finally, addition of 1 micromol/l exendin-(9-39)-amide to 20 mmol/l glucose-stimulated beta-cells did not antagonize the potentiating effect of 1 nmol/l glucagon, although it prevented 45% of glucagon potentiation when the peptide was administered at 10 nmol/l. Our data suggest that glucagon recognition via two distinct receptors allows pancreatic beta-cells to detect this peptide both when diluted in the systemic circulation and when concentrated as local signal in the islet interstitium.

Published
1998

158. Celiac Disease

Author

Flamez, Brandé, primary, Clark, Ashley A., additional, and Sheperis, Carl J., additional

Published
2013
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159. Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis.

Author

Cnop, Miriam, Ladrière, Laurence, Hekerman, Paul, Ortis, Fernanda, Dogusan, Zeynep, Flamez, Daisy, Boyce, M., Yuan, J., Eizirik, Decio L., Cardozo, Alessandra K, Cnop, Miriam, Ladrière, Laurence, Hekerman, Paul, Ortis, Fernanda, Dogusan, Zeynep, Flamez, Daisy, Boyce, M., Yuan, J., Eizirik, Decio L., and Cardozo, Alessandra K

Abstract

Free fatty acids cause pancreatic beta-cell apoptosis and may contribute to beta-cell loss in type 2 diabetes via the induction of endoplasmic reticulum stress. Reductions in eukaryotic translation initiation factor (eIF) 2alpha phosphorylation trigger beta-cell failure and diabetes. Salubrinal selectively inhibits eIF2alpha dephosphorylation, protects other cells against endoplasmic reticulum stress-mediated apoptosis, and has been proposed as a beta-cell protector. Unexpectedly, salubrinal induced apoptosis in primary beta-cells, and it potentiated the deleterious effects of oleate and palmitate. Salubrinal induced a marked eIF2alpha phosphorylation and potentiated the inhibitory effects of free fatty acids on protein synthesis and insulin release. The synergistic activation of the PERK-eIF2alpha branch of the endoplasmic reticulum stress response, but not of the IRE1 and activating transcription factor-6 pathways, led to a marked induction of activating transcription factor-4 and the pro-apoptotic transcription factor CHOP. Our findings demonstrate that excessive eIF2alpha phosphorylation is poorly tolerated by beta-cells and exacerbates free fatty acid-induced apoptosis. This modifies the present paradigm regarding the beneficial role of eIF2alpha phosphorylation in beta-cells and must be taken into consideration when designing therapies to protect beta-cells in type 2 diabetes., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2007

160. T1DBase: integration and presentation of complex data for type 1 diabetes research.

Author

Hulbert, Erin M, Smink, Luc J, Adlem, Ellen C, Allen, James E, Burdick, David B, Burren, Oliver S, Cassen, Victor M, Cavnor, C., Dolman, Geoffrey E, Flamez, Daisy, Friery, Karen F, Healy, Barry C, Killcoyne, Sarah A, Kutlu, Burak, Schuilenburg, Helen, Walker, Neil M, Mychaleckyj, Josyf, Eizirik, Decio L., Wicker, Linda S, Todd, John A, Goodman, N., Hulbert, Erin M, Smink, Luc J, Adlem, Ellen C, Allen, James E, Burdick, David B, Burren, Oliver S, Cassen, Victor M, Cavnor, C., Dolman, Geoffrey E, Flamez, Daisy, Friery, Karen F, Healy, Barry C, Killcoyne, Sarah A, Kutlu, Burak, Schuilenburg, Helen, Walker, Neil M, Mychaleckyj, Josyf, Eizirik, Decio L., Wicker, Linda S, Todd, John A, and Goodman, N.

Abstract

T1DBase (http://T1DBase.org) [Smink et al. (2005) Nucleic Acids Res. 33, D544-D549; Burren et al. (2004) Hum. Genomics, 1, 98-109] is a public website and database that supports the type 1 diabetes (T1D) research community. T1DBase provides a consolidated T1D-oriented view of the complex data world that now confronts medical researchers and enables scientists to navigate from information they know to information that is new to them. Overview pages for genes and markers summarize information for these elements. The Gene Dossier summarizes information for a list of genes. GBrowse [Stein et al. (2002) Genome Res. 10, 1599-1610] displays genes and other features in their genomic context, and Cytoscape [Shannon et al. (2003) Genome Res. 13, 2498-2504] shows genes in the context of interacting proteins and genes. The Beta Cell Gene Atlas shows gene expression in beta cells, islets, and related cell types and lines, and the Tissue Expression Viewer shows expression across other tissues. The Microarray Viewer shows expression from more than 20 array experiments. The Beta Cell Gene Expression Bank contains manually curated gene and pathway annotations for genes expressed in beta cells. T1DMart is a query tool for markers and genotypes. PosterPages are 'home pages' about specific topics or datasets. The key challenge, now and in the future, is to provide powerful informatics capabilities to T1D scientists in a form they can use to enhance their research., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2007

161. Disruption of the gamma-interferon signaling pathway at the level of signal transducer and activator of transcription-1 prevents immune destruction of beta-cells.

Author

Gysemans CA, Ladrière L, Callewaert H, Rasschaert J, Flamez D, Levy DE, Matthys P, Eizirik DL, Mathieu C, Gysemans, Conny A, Ladrière, Laurence, Callewaert, Hanne, Rasschaert, Joanne, Flamez, Daisy, Levy, David E, Matthys, Patrick, Eizirik, Décio L, and Mathieu, Chantal

Abstract

beta-cells under immune attack are destroyed by the aberrant activation of key intracellular signaling cascades. The aim of the present study was to evaluate the contribution of the signal transducer and activator of transcription (STAT)-1 pathway for beta-cell apoptosis by studying the sensitivity of beta-cells from STAT-1 knockout (-/-) mice to immune-mediated cell death in vitro and in vivo. Whole islets from STAT-1-/- mice were completely resistant to interferon (IFN)-gamma (studied in combination with interleukin [IL]-1beta)-mediated cell death (92 +/- 4% viable cells in STAT-1-/- mice vs. 56 +/- 3% viable cells in wild-type controls, P < or = 0.001) and had preserved insulin release after exposure to IL-1beta and IFN-gamma. Moreover, analysis of cell death in cytokine-exposed purified beta-cells confirmed that protection was due to absence of STAT-1 in the beta-cells themselves. Deficiency of STAT-1 in islets completely prevented cytokine-induced upregulation of IL-15, interferon inducible protein 10, and inducible nitric oxide synthase transcription but did not interfere with monocyte chemoattractant protein 1 and macrophage inflammatory protein 3alpha expression. In vivo, STAT-1-/- mice were partially resistant to development of diabetes after multiple low-dose streptozotocin injections as reflected by mean blood glucose at 12 days after first injection (159 +/- 28 vs. 283 +/- 81 mg/dl in wild-type controls, P < or = 0.05) and diabetes incidence at the end of the follow-up period (39 vs. 73% in wild-type controls, P < or = 0.05). In conclusion, the present results indicate that STAT-1 is a crucial transcription factor in the process of IFN-gamma-mediated beta-cell death and the subsequent development of immune-mediated diabetes. [ABSTRACT FROM AUTHOR]

Published
2005
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163. Pharmacological characterization of I1 and I2 imidazoline receptors in human striatum

Author

Georges Vauquelin, Anja Flamez, Jean-Paul De Backer, Eva Czerwiec, Philippe Ladure, Molecular and Biochemical Pharmacology, Faculty of Medicine and Pharmacy, Neuroprotection & Neuromodulation, Neurology, and Vrije Universiteit Brussel

Subjects
Male, Adrenergic receptor, Stereochemistry, Receptors, Drug, Imidazoline receptor, Clonidine, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Structure-Activity Relationship, Allosteric Regulation, Idazoxan, medicine, Humans, Receptor, Adrenergic alpha-Antagonists, Aged, Cell Biology, Middle Aged, Efaroxan, Cirazoline, Corpus Striatum, Benzodioxan, nervous system, chemistry, Biochemistry, Female, Imidazoline Receptors, medicine.drug
Abstract

[ 3 H]RX821002, [ 3 H]clonidine and [ 3 H]idazoxan have previously been shown to selectively label α 2 -adrenergic receptors, I 1 and I 2 imidazoline receptors in the human central nervous system, respectively. Idazoxan shows relatively high affinity for all three receptors. We investigated the possible selectivity of several compounds towards one of those receptors in human striatum. Addition of an alkoxy group at the 2-position of the benzodioxan moiety of idazoxan (ethoxy-idazoxan, methoxy-idazoxan) increases the α 2 -selectivity in human brain. Efaroxan is also α 2 -selective. On the contrary, BU224, BU239, cirazoline and RX801077 display imidazoline receptor selectivity. Our results indicate that for all molecules tested, idazoxan and ‘flat’ analogs possess I 1 I 2 receptor selectivity. A ‘bulky’ substituent at the 2-position of the benzodioxan ring gives rise to α 2 -adrenergic receptor selectivity. Until now, we found no more than 3-fold difference in IC 50 between both imidazoline receptors. Both receptors also display similar stereoselectivity, suggesting that they might be ‘interconnected’ in the human striatum.

Published
1997

166. Detection of motor and non-motor symptoms of end-of dose wearing-off in Parkinson's disease using a dedicated questionnaire: A Belgian multicenter survey

Author

Santens, Patrick, de Noordhout, Alain Maertens, Cras, Patrick, Dethy, Sophie, Flamez, Anja, Gonce, Michel, Jeanjean, Anne, Pickut, Barbara, Supiot, Frédéric, Vandenberghe, Wim, Vanderheyden, Jean-Emile, Van Der Linden, Chris, Van Zandijcke, Michel, Santens, Patrick, de Noordhout, Alain Maertens, Cras, Patrick, Dethy, Sophie, Flamez, Anja, Gonce, Michel, Jeanjean, Anne, Pickut, Barbara, Supiot, Frédéric, Vandenberghe, Wim, Vanderheyden, Jean-Emile, Van Der Linden, Chris, and Van Zandijcke, Michel

Abstract

In this report the usefulness of a dedicated questionnaire to detect end-of-dose wearing-off (EODWO) fluctuations in PD was studied. One hundred and sixty patients were administered an 18-item questionnaire encompassing both motor and non-motor phenomena. One hundred and eight (86%) reported EODWO, defined as the occurrence of at least one symptom improving by drug intake. Motor phenomena were significantly more frequent and non-motor phenomena never occurred in isolation. This questionnaire was deemed useful by most participants., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2006

168. T1DBase, a community web-based resource for type 1 diabetes research.

Author

Smink, Luc J, Helton, E., Healy, Barry C, Cavnor, C., Lam, Alex C, Flamez, Daisy, Burren, Oliver S, Wang, Yue, Dolman, Geoffrey E, Burdick, David B, Everett, Vincent H, Glusman, Gustavo, Laneri, Davide, Rowen, Lee, Schuilenburg, Helen, Walker, Neil M, Mychaleckyj, Josyf, Wicker, Linda S, Eizirik, Decio L., Todd, John A, Goodman, N., Smink, Luc J, Helton, E., Healy, Barry C, Cavnor, C., Lam, Alex C, Flamez, Daisy, Burren, Oliver S, Wang, Yue, Dolman, Geoffrey E, Burdick, David B, Everett, Vincent H, Glusman, Gustavo, Laneri, Davide, Rowen, Lee, Schuilenburg, Helen, Walker, Neil M, Mychaleckyj, Josyf, Wicker, Linda S, Eizirik, Decio L., Todd, John A, and Goodman, N.

Abstract

T1DBase (http://T1DBase.org) is a public website and database that supports the type 1 diabetes (T1D) research community. The site is currently focused on the molecular genetics and biology of T1D susceptibility and pathogenesis. It includes the following datasets: annotated genome sequence for human, rat and mouse; information on genetically identified T1D susceptibility regions in human, rat and mouse, and genetic linkage and association studies pertaining to T1D; descriptions of NOD mouse congenic strains; the Beta Cell Gene Expression Bank, which reports expression levels of genes in beta cells under various conditions, and annotations of gene function in beta cells; data on gene expression in a variety of tissues and organs; and biological pathways from KEGG and BioCarta. Tools on the site include the GBrowse genome browser, site-wide context dependent search, Connect-the-Dots for connecting gene and other identifiers from multiple data sources, Cytoscape for visualizing and analyzing biological networks, and the GESTALT workbench for genome annotation. All data are open access and all software is open source., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2005

169. Disruption of the gamma-interferon signaling pathway at the level of signal transducer and activator of transcription-1 prevents immune destruction of beta-cells.

Author

Gysemans, Conny A, Ladrière, Laurence, Callewaert, Hanne, Rasschaert, Joanne, Flamez, Daisy, Levy, David E, Matthys, Patrick, Eizirik, Decio L., Mathieu, Chantal, Gysemans, Conny A, Ladrière, Laurence, Callewaert, Hanne, Rasschaert, Joanne, Flamez, Daisy, Levy, David E, Matthys, Patrick, Eizirik, Decio L., and Mathieu, Chantal

Abstract

beta-cells under immune attack are destroyed by the aberrant activation of key intracellular signaling cascades. The aim of the present study was to evaluate the contribution of the signal transducer and activator of transcription (STAT)-1 pathway for beta-cell apoptosis by studying the sensitivity of beta-cells from STAT-1 knockout (-/-) mice to immune-mediated cell death in vitro and in vivo. Whole islets from STAT-1-/- mice were completely resistant to interferon (IFN)-gamma (studied in combination with interleukin [IL]-1beta)-mediated cell death (92 +/- 4% viable cells in STAT-1-/- mice vs. 56 +/- 3% viable cells in wild-type controls, P < or = 0.001) and had preserved insulin release after exposure to IL-1beta and IFN-gamma. Moreover, analysis of cell death in cytokine-exposed purified beta-cells confirmed that protection was due to absence of STAT-1 in the beta-cells themselves. Deficiency of STAT-1 in islets completely prevented cytokine-induced upregulation of IL-15, interferon inducible protein 10, and inducible nitric oxide synthase transcription but did not interfere with monocyte chemoattractant protein 1 and macrophage inflammatory protein 3alpha expression. In vivo, STAT-1-/- mice were partially resistant to development of diabetes after multiple low-dose streptozotocin injections as reflected by mean blood glucose at 12 days after first injection (159 +/- 28 vs. 283 +/- 81 mg/dl in wild-type controls, P < or = 0.05) and diabetes incidence at the end of the follow-up period (39 vs. 73% in wild-type controls, P < or = 0.05). In conclusion, the present results indicate that STAT-1 is a crucial transcription factor in the process of IFN-gamma-mediated beta-cell death and the subsequent development of immune-mediated diabetes., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2005

170. Production in Escherichia coli of a functional murine and murine::human chimeric F(ab')2 fragment and mature antibody directed against human placental alkaline phosphatase

Author

Daisy Flamez, Erik Remaut, and Walter Fiers

Subjects
DNA, Complementary, medicine.drug_class, Placenta, Genetic Vectors, Molecular Sequence Data, Bioengineering, Biology, medicine.disease_cause, Monoclonal antibody, Immunoglobulin light chain, Applied Microbiology and Biotechnology, law.invention, Immunoglobulin Fab Fragments, Mice, law, Complementary DNA, medicine, Biomarkers, Tumor, Escherichia coli, Animals, Humans, Cloning, Molecular, Base Sequence, General Medicine, Alkaline Phosphatase, Molecular biology, Recombinant Proteins, Placental alkaline phosphatase, Biochemistry, Immunoglobulin G, Recombinant DNA, biology.protein, Alkaline phosphatase, Antibody, Biotechnology
Abstract

We report the production in Escherichia coli of a murine antibody IgG2b, a murine::human chimeric antibody IgG3 and the corresponding F(ab′) 2 fragments, all directed against human placental alkaline phosphatase, a tumor marker. The cDNA of the heavy chain of the mature antibodies and their fragments were linked up to the bacterial alkaline phosphatase signal sequence and were placed under control of the inducible tac promoter. Coexpression with the murine κ light chain resulted in production of functional dimeric, trimeric and tetrameric, mature antibodies and F(ab′) 2 fragments in the periplasm of E. coli in a yield of 200–300 μg 1 −1 . High amounts of light and heavy chains were present also in the insoluble fraction.

Published
1995

173. The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity

Author

Viollet, Benoit, Andreelli, Fabrizio, Jørgensen, Sebastian B., Perrin, Christophe, Geloen, Alain, Flamez, Daisy, Mu, James, Lenzner, Claudia, Baud, Olivier, Bennoun, Myriam, Gomas, Emmanuel, Nicolas, Gaël, Wojtaszewski, Jørgen, Kahn, Axel, Carling, David, Schuit, Frans C., Birnbaum, Morris J., Richter, Erik A., Burcelin, Rémy, Vaulont, Sophie, Viollet, Benoit, Andreelli, Fabrizio, Jørgensen, Sebastian B., Perrin, Christophe, Geloen, Alain, Flamez, Daisy, Mu, James, Lenzner, Claudia, Baud, Olivier, Bennoun, Myriam, Gomas, Emmanuel, Nicolas, Gaël, Wojtaszewski, Jørgen, Kahn, Axel, Carling, David, Schuit, Frans C., Birnbaum, Morris J., Richter, Erik A., Burcelin, Rémy, and Vaulont, Sophie

Published
2003

174. Physiological role of AMP-activated protein kinase (AMPK): insights from knockout mouse models

Author

Viollet, B., Andreelli, F., Jørgensen, Sebastian Beck, Perrin, C., Flamez, D., Mu, J., Wojtaszewski, Jørgen, Schuit, F. C., Birnbaum, M., Richter, Erik A., Burcelin, R., Vaulont, S., Viollet, B., Andreelli, F., Jørgensen, Sebastian Beck, Perrin, C., Flamez, D., Mu, J., Wojtaszewski, Jørgen, Schuit, F. C., Birnbaum, M., Richter, Erik A., Burcelin, R., and Vaulont, S.

Published
2003

175. [3H]Clozapine is not a suitable radioligand for the labelling of D4 dopamine receptors in postmortem human brain

Author

Jacques De Keyser, Georges Vauquelin, N. Wilczak, Jean-Paul De Backer, Anja Flamez, Faculty of Medicine and Pharmacy, Neuroprotection & Neuromodulation, Neurology, and Gerontology

Subjects
Male, Clozapine/*metabolism, Imidazoline receptor, receptors, Pharmacology, Ligands, Receptors, Dopamine, Middle Age, Radioligand Assay, Competitive, Radioligand, Catecholamine uptake, Brain Chemistry, Clozapine, Substantia Nigra/chemistry/metabolism, support, Chemistry, General Neuroscience, Brain, Middle Aged, Amygdala/chemistry/metabolism, Amygdala, Radioligand Assay/methods, Frontal Lobe, Substantia Nigra, Dopamine receptor, Organ Specificity, Female, Brain/*metabolism, Cell Membrane/*metabolism, medicine.drug, Frontal Lobe/chemistry/metabolism, Human, medicine.medical_specialty, Tritium, Binding, Competitive, Dopamine agonist, autopsy, Dopamine, Internal medicine, medicine, Humans, Aged, Corpus Striatum/chemistry/metabolism, Receptors, Dopamine D2, Cell Membrane, Receptors, Dopamine D4, Binding, Corpus Striatum, Apomorphine, Endocrinology, kinetics, Dopamine/analysis/*metabolism, Serotonin
Abstract

Clozapine displays nanomolar affinity for cloned human D 4 -type dopamine receptors expressed in tissue culture cells. Therefore, [ 3 H]clozapine has been introduced as a radioligand for the labelling of the D 4 dopamine receptors. We found that, in membranes of postmortem human striatum, amygdala, frontal cortex and substantia nigra, neither dopamine nor the dopamine agonist apomorphine displaced the binding of [ 3 H]clozapine (5–20 nM). [ 3 H]Clozapine competition curves with clozapine and loxapine revealed the presence of two binding sites. The high-affinity site was displaced by atropine and pirenzepine with nanomolar affinity. The low-affinity site did not correspond to a serotonin, adrenergic, γ-amino butyric acid, N- methyl - d - aspartate , benzodiazepine, histamine, sigma, imidazoline receptor-binding site, or catecholamine uptake site. Our results suggest that [ 3 H]clozapine in post-mortem human brain binds to M 1 -type muscarinic cholinergic receptors and to a low-affinity binding site but is not a suitable radioligand for investigating the D 4 dopamine receptors.

Published
1994

176. Autoradiographic distribution of D3-type dopamine receptors in human brain using [3H]7-hydroxy-N,N-di-n-propyl-2-aminotetralin

Author

Georges Vauquelin, J P De Backer, J. De Keyser, Anja Flamez, Luc Herroelen, N. Wilczak, Gerontology, Faculty of Medicine and Pharmacy, Neuroprotection & Neuromodulation, and Neurology

Subjects
Male, medicine.medical_specialty, Brain Chemistry/*physiology, Tetrahydronaphthalenes, receptors, Substantia nigra, Nucleus accumbens, Dopamine/drug effects/*metabolism, Middle Age, Receptors, Dopamine, Dopamine, Internal medicine, medicine, Humans, Molecular Biology, In Situ Hybridization, Aged, Brain Chemistry, Chemistry, Receptors, Dopamine D2, General Neuroscience, Dopaminergic, Tetrahydronaphthalenes/*diagnostic use/pharmacokin, Receptors, Dopamine D3, Brain/*anatomy & histology, Brain, Human brain, Middle Aged, medicine.anatomical_structure, Endocrinology, Globus pallidus, nervous system, Cerebral cortex, Dopamine receptor, Autoradiography, Female, Neurology (clinical), Human, Developmental Biology, medicine.drug
Abstract

The regional distribution of D3 dopamine receptors was studied in human brain by quantitative autoradiography with [3H]7-hydroxy-N,N-di-n-propyl-2-aminotetralin ([3H]7-OH-DPAT). The highest densities were found in the ventral striatum/nucleus accumbens, followed by the remainder of the neostriatum, cerebral cortex, and cerebellar cortex. Moderate amounts were found in the substantia nigra. Low densities of D3 dopamine receptors were visualized in pituitary gland (posterior lobe > anterior lobe), amygdala, and hippocampus. The globus pallidus and thalamus contained lower densities. The distribution pattern is much more widespread as detected by in situ hybridisation histochemistry for D3 mRNA in human and in rat brain. Our data confirm a predilection of D3 receptors in brain areas involved in cognitive and emotional functions. The presence of D3 receptors in non-limbic parts of the neostriatum and substantia nigra suggests that they also play a role in the dopaminergic control of motor processes. Its precise function in cerebellum and pituitary gland is at present uncertain.

Published
1994

178. Cytokines Interleukin-1β and Tumor Necrosis Factor-α Regulate Different Transcriptional and Alternative Splicing Networks in Primary β-Cells

Author

Ortis, Fernanda, primary, Naamane, Najib, additional, Flamez, Daisy, additional, Ladrière, Laurence, additional, Moore, Fabrice, additional, Cunha, Daniel A., additional, Colli, Maikel L., additional, Thykjaer, Thomas, additional, Thorsen, Kasper, additional, Ørntoft, Torben F., additional, and Eizirik, Decio L., additional

Published
2009
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184. Altered cAMP and Ca2+ signaling in mouse pancreatic islets with glucagon-like peptide-1 receptor null phenotype

Author

UCL - MD/FSIO - Département de physiologie et pharmacologie, Flamez, Daisy, Gilon, Patrick, Moens, Karen, Van Breusegem, An, Delmeire, Dominique, Scrocchi, Louise A, Henquin, Jean-Claude, Drucker, Daniel J., Schuit, Francis C., UCL - MD/FSIO - Département de physiologie et pharmacologie, Flamez, Daisy, Gilon, Patrick, Moens, Karen, Van Breusegem, An, Delmeire, Dominique, Scrocchi, Louise A, Henquin, Jean-Claude, Drucker, Daniel J., and Schuit, Francis C.

Abstract

1-Cells from rodents and humans express different receptors recognizing hormones of the secretin-glucagon family, which--when activated--synergize with glucose in the control of insulin release. We have recently reported that isolated islets from mice homozygous for a GLP-1 receptor null mutation (GLP-1R(-/-)) exhibit a well-preserved insulin-secretory response to glucose. This observation can be interpreted in two different ways: 1) the presence of GLP-1R is not essential for the secretory response of isolated islets to glucose alone; 2) beta-cells in GLP-1R(-/-) pancreases underwent compensatory changes in response to the null mutation. To explore these possibilities, we studied islets from control GLP-IR(+/+) mice in the absence or presence of 1 pmol/l exendin (9-39)amide, a specific and potent GLP-1R antagonist. Exendin (9-39)amide (15-min exposure) reduced glucose-induced insulin secretion from both perifused and statically incubated GLP-1R(+/+) islets by 50% (P < 0.05), and reduced islet cAMP production in parallel (P < 0.001). Furthermore, GLP-1R(-/-) islets exhibited: 1) reduced cAMP accumulation in the presence of 20 mmol/l glucose (knockout islets versus control islets, 12 +/- 1 vs. 27 +/- 3 fmol x islet(-1) x 15 min(-1); P < 0.001) and exaggerated acceleration of cAMP production by 10 nmol/l glucose-dependent insulinotropic peptide (GIP) (increase over 20 mmol/l glucose by GIP in knockout islets versus control islets: 66 +/- 5 vs. 14 +/- 3 fmol x islet(-1) x 15 min(-1); P < 0.001); 2) increased mean cytosolic [Ca2+] ([Ca2+]c) at 7, 10, and 15 mmol/l glucose in knockout islets versus control islets; and 3) signs of asynchrony of [Ca2+]c oscillations between different islet subregions. In conclusion, disruption of GLP-1R signaling is associated with reduced basal but enhanced GIP-stimulated cAMP production and abnormalities in basal and glucose-stimulated [Ca2+]c. These abnormalities suggest that GLP-1R signaling is an essential upstream component of multip

Published
1999

185. Alterations of cytoplasmic Ca2+ regulation in mouse islets unresponsive to GLP-1

Author

UCL - MD/FSIO - Département de physiologie et pharmacologie, Gilon, Patrick, Flamez, D., Van Breuseghem, A., Schrocchi, L., Drucker, DJ, Henquin, Jean-Claude, Schuit, Frans C., 34th Annual Meeting of the European Association for the Study of Diabetes, UCL - MD/FSIO - Département de physiologie et pharmacologie, Gilon, Patrick, Flamez, D., Van Breuseghem, A., Schrocchi, L., Drucker, DJ, Henquin, Jean-Claude, Schuit, Frans C., and 34th Annual Meeting of the European Association for the Study of Diabetes

Published
1998

188. Hypoglycemia, defective islet glucagon secretion, but normal islet mass in mice with a disruption of the gastrin gene1 1The authors thank Emmy De Blay and Luc Bouwens for generous assistance with islet immunohistochemistry.

Author

Boushey, Robin P, primary, Abadir, Amir, additional, Flamez, Daisy, additional, Baggio, Laurie L, additional, Li, Yazhou, additional, Berger, Veerle, additional, Marshall, Bess A, additional, Finegood, Diane, additional, Wang, Timothy C, additional, Schuit, Frans, additional, and Drucker, Daniel J, additional

Published
2003
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190. A Globin in the Nucleus!

Author

Geuens, Eva, primary, Brouns, Inge, additional, Flamez, Daisy, additional, Dewilde, Sylvia, additional, Timmermans, Jean-Pierre, additional, and Moens, Luc, additional

Published
2003
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192. The AMP-activated protein kinase α2 catalytic subunit controls whole-body insulin sensitivity

Author

Viollet, Benoit, primary, Andreelli, Fabrizio, additional, Jørgensen, Sebastian B., additional, Perrin, Christophe, additional, Geloen, Alain, additional, Flamez, Daisy, additional, Mu, James, additional, Lenzner, Claudia, additional, Baud, Olivier, additional, Bennoun, Myriam, additional, Gomas, Emmanuel, additional, Nicolas, Gaël, additional, Wojtaszewski, Jørgen F.P., additional, Kahn, Axel, additional, Carling, David, additional, Schuit, Frans C., additional, Birnbaum, Morris J., additional, Richter, Erik A., additional, Burcelin, Rémy, additional, and Vaulont, Sophie, additional

Published
2003
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193. Mouse pancreatic beta-cells exhibit preserved glucose competence after disruption of the glucagon-like peptide-1 receptor gene.

Author

Flamez, Daisy, Van Breusegem, An, Scrocchi, Louise A., Quartier, Erik, Pipeleers, Daniel, Drucker, Daniel J., Schuit, Frans, Flamez, D, Van Breusegem, A, Scrocchi, L A, Quartier, E, Pipeleers, D, Drucker, D J, and Schuit, F

Subjects
*PEPTIDES, *ISLANDS of Langerhans
Abstract

Previous work suggested that glucagon-like peptide 1 (GLP-1) can acutely regulate insulin secretion in two ways, 1) by acting as an incretin, causing amplification of glucose-induced insulin release when glucose is given orally as opposed to intravenous glucose injection; and 2) by keeping the beta-cell population in a glucose-competent state. The observation that mice with homozygous disruption of the GLP-1 receptor gene are diabetic with a diminished incretin response to glucose underlines the first function in vivo. Isolated islets of Langerhans from GLP-1 receptor -/- mice were studied to assess the second function in vitro. Absence of pancreatic GLP-1 receptor function was observed in GLP-1 receptor -/- mice, as exemplified by loss of [125I]GLP-1 binding to pancreatic islets in situ and by the lack of GLP-1 potentiation of glucose-induced insulin secretion from perifused islets. Acute glucose competence of the beta-cells, assessed by perifusing islets with stepwise increases of the medium glucose concentration, was well preserved in GLP-1 receptor -/- islets in terms of insulin secretion. Furthermore, neither islet nor total pancreatic insulin content was significantly changed in the GLP-1 receptor -/- mice when compared with age-and sex-matched controls. In conclusion, mouse islets exhibit preserved insulin storage capacity and glucose-dependent insulin secretion despite the loss of functional GLP-1 receptors. The results demonstrate that the glucose responsiveness of islet beta-cells is well preserved in the absence of GLP-1 receptor signaling. [ABSTRACT FROM AUTHOR]

Published
1998
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194. Dual glucagon recognition by pancreatic beta-cells via glucagon and glucagon-like peptide 1 receptors.

Author

Moens, Karen, Flamez, Daisy, Van Schravendijk, C., Ling, Z., Pipeleers, D., Schuit, F., Moens, K, and Flamez, D

Subjects
*GLUCAGON, *PEPTIDES, *PANCREATIC beta cells
Abstract

cAMP is required for normal glucose-induced insulin release by pancreatic beta-cells. In a previous study, we showed that cAMP production in beta-cells depends on the expression of receptors for glucagon, glucagon-like peptide 1(7-36) amide [GLP-1(7-36) amide], and glucose-dependent insulinotropic polypeptide. Although the latter two peptides are thought to amplify meal-induced insulin release (incretin effect), the role of glucagon in the regulation of insulin release remains elusive. In the present study, we analyzed the interaction of glucagon with its own receptor and with the glucagon-like peptide 1 (GLP-1) receptor using purified rat beta-cells. Glucagon binding was partially displaced by 1 micromol/l des-His1-[Glu9]glucagon-amide, a glucagon receptor antagonist, and by 1 micromol/l GLP-1. Conversely, GLP-1 binding was competitively inhibited by high glucagon concentrations (Ki = 0.3 micromol/l). Glucagon-induced cAMP production in beta-cells was inhibited both by 1 micromol/l des-His1-[Glu9]glucagon-amide and exendin-(9-39)-amide, a specific GLP-1 receptor antagonist, whereas GLP-1-induced cAMP formation was suppressed only by exendin-(9-39)-amide. Finally, addition of 1 micromol/l exendin-(9-39)-amide to 20 mmol/l glucose-stimulated beta-cells did not antagonize the potentiating effect of 1 nmol/l glucagon, although it prevented 45% of glucagon potentiation when the peptide was administered at 10 nmol/l. Our data suggest that glucagon recognition via two distinct receptors allows pancreatic beta-cells to detect this peptide both when diluted in the systemic circulation and when concentrated as local signal in the islet interstitium. [ABSTRACT FROM AUTHOR]

Published
1998
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195. Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor -/- mice.

Author

Pederson, Raymond A., Satkunarajah, Malathy, McIntosh, Christopher H.S., Scrocchi, Louise A., Flamez, Daisy, Schuit, Frans, Drucker, Daniel J., Wheeler, Michael B., Pederson, R A, Satkunarajah, M, McIntosh, C H, Scrocchi, L A, Flamez, D, Schuit, F, Drucker, D J, and Wheeler, M B

Subjects
PEPTIDES, INSULIN, GASTROINTESTINAL system, SECRETION
Abstract

Incretins are gastrointestinal hormones that act on the pancreas to potentiate glucose-stimulated insulin secretion. Despite the physiological importance of the enteroinsular axis, disruption of glucagon-like peptide (GLP)-1 action is associated with only modest glucose intolerance in GLP-1 receptor -/- (GLP-1R -/-) mice. We show here that GLP-1R -/- mice exhibit compensatory changes in the enteroinsular axis via increased glucose-dependent insulinotropic polypeptide (GIP) secretion and enhanced GIP action. Serum GIP levels in GLP-1R -/- mice were significantly elevated versus those in +/+ control mice after an oral glucose tolerance test (369 +/- 40 vs. 236 +/- 28 pmol/l; P < or = 0.02). Furthermore, GIP perfusion of mice pancreas and isolated islets in the presence of elevated glucose concentrations elicited a significantly greater insulin response in GLP-1R -/- than in +/+ mice (P < or = 0.02-0.05). In contrast, no significant perturbation in the insulin response to perfused glucagon was detected under conditions of low (4.4 mmol/l) or high (16.6 mmol/l) glucose in GLP-1R -/- mice. Total pancreatic insulin but not glucagon content was significantly reduced in GLP-1R -/- compared with in +/+ mice (77 +/- 9 vs. 121 +/- 10 pmol/mg protein; P < or = 0.005). These observations suggest that upregulation of the GIP component of the enteroinsular axis, at the levels of GIP secretion and action, modifies the phenotype resulting from interruption of the insulinotropic activity of GLP-1 in vivo. [ABSTRACT FROM AUTHOR]

Published
1998
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197. Two-Component System Regulon Plasticity in Bacteria: A Concept Emerging from Phenotypic Analysis of Yersinia pseudotuberculosis Response Regulator Mutants.

Author

Back, Nathan, Cohen, Irun R., Kritchevsky, David, Lajtha, Abel, Paoletti, Rodolfo, Perry, Robert D., Fetherston, Jacqueline D., Flamez, Claire, Marceau, Michaël, Simonet, Michel, Arafah, Sonia, and Ricard, Isabelle

Abstract

In bacteria, the most rapid and efficient means of adapting gene transcription to extracellular stresses often involves sophisticated systems referred to as two-component systems (2CSs). Although highly conserved throughout the bacterial world, some of these systems may control distinct cell events and have differing contributions to virulence, depending on the species considered. This chapter summarizes the work performed by our group - from the initial PhoP-PhoQ and PmrA-PmrB studies to the most recent genome-scale preliminary analyses - in an attempt to highlight the contribution of 2CS regulon plasticity to the acquisition of some of Yersinia pseudotuberculosis' specific features. [ABSTRACT FROM AUTHOR]

Published
2008
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200. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model

Author

Ilse Dewachter, Kristina Endres, Rolf Postina, Anja Schroeder, Antoine Dequenne, Fred Van Leuven, Falk Fahrenholz, Elzbieta Kojro, Christoph Hiemke, Pascaline Flamez, Manfred Blessing, Claudia Prinzen, Juergen Bohl, Ulrich Schmitt, and Emile Godaux

Subjects
Genetically modified mouse, Pathology, medicine.medical_specialty, Amyloid, ADAM10, BACE1-AS, Gene Expression, Mice, Transgenic, Hippocampus, Article, Amyloid beta-Protein Precursor, Mice, Alzheimer Disease, Endopeptidases, Amyloid precursor protein, medicine, Animals, Aspartic Acid Endopeptidases, Humans, biology, business.industry, P3 peptide, Amyloidosis, General Medicine, medicine.disease, Cell biology, Enzyme Activation, Disease Models, Animal, Commentary, biology.protein, Erratum, Alzheimer's disease, Amyloid Precursor Protein Secretases, business, Amyloid precursor protein secretase
Abstract

Alzheimer disease (AD) is characterized by excessive deposition of amyloid beta-peptides (A beta peptides) in the brain. In the nonamyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by the alpha-secretase within the A beta peptide sequence. Proteinases of the ADAM family (adisintegrin and metalloproteinase) are the main candidates as physiologically relevant alpha-secretases, but early lethality of knockout animals prevented a detailed analysis in neuronal cells. To overcome this restriction, we have generated transgenic mice that overexpress either ADAM10 or a catalytically inactive ADAM10 mutant. In this report we show that a moderate neuronal overexpression of ADAM10 in mice transgenic for human APP([V717I]) increased the secretion of the neurotrophic soluble alpha-secretase-released N-terminal APP domain (APPs alpha), reduced the formation of A beta peptides, and prevented their deposition in plaques. Functionally, impaired long-term potentiation and cognitive deficits were alleviated. Expression of mutant catalytically inactive ADAM10 led to an enhancement of the number and size of amyloid plaques in the brains of double-transgenic mice. The results provide the first in vivo evidence for a proteinase of the ADAM family as an alpha-secretase of APP, reveal activation of ADAM10 as a promising therapeutic target, and support the hypothesis that a decrease in alpha-secretase activity contributes to the development of AD.

Published
2004
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