CD33 Alzheimer's Risk-Altering Polymorphism, CD33 Expression, and Exon 2 Splicing
Manasi Malik,James F. Simpson,Ishita Parikh,Bernard R. Wilfred,David W. Fardo,Peter T. Nelson,Steven Estus +6 more
TLDR
This work elucidates the mechanism of action of the AD-associated polymorphism rs3865444 in the promoter of CD33, a member of the sialic acid-binding Ig-superfamily of lectins (SIGLECs) and suggests a novel model wherein SNP-modulated RNA splicing modulates CD33 function and, thereby, AD risk.Abstract:
Genome-wide association studies are identifying novel Alzheimer's disease (AD) risk factors. Elucidating the mechanism underlying these polymorphisms is critical to the validation process and, by identifying rate-limiting steps in AD risk, may yield novel therapeutic targets. Here, we elucidate the mechanism of action of the AD-associated polymorphism rs3865444 in the promoter of CD33, a member of the sialic acid-binding Ig-superfamily of lectins (SIGLECs). Immunostaining established that CD33 is expressed in microglia in human brain. Consistent with this finding, CD33 mRNA expression correlated well with expression of the microglial genes CD11b and AIF-1 and was modestly increased with AD status and the rs3865444C AD-risk allele. Analysis of CD33 isoforms identified a common isoform lacking exon 2 (D2-CD33). The proportion of CD33 expressed as D2-CD33 correlated robustly with rs3865444 genotype. Because rs3865444 is in the CD33 promoter region, we sought the functional polymorphism by sequencing CD33 from the promoter through exon 4. We identified a single polymorphism that is coinherited with rs3865444, i.e., rs12459419 in exon 2. Minigene RNA splicing studies in BV2 microglial cells established that rs12459419 is a functional single nucleotide polymorphism (SNP) that modulates exon 2 splicing efficiency. Thus, our primary findings are that CD33 is a microglial mRNA and that rs3865444 is a proxy SNP for rs12459419 that modulates CD33 exon 2 splicing. Exon 2 encodes the CD33 IgV domain that typically mediates sialic acid binding in SIGLEC family members. In summary, these results suggest a novel model wherein SNP-modulated RNA splicing modulates CD33 function and, thereby, AD risk.read more
Citations
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Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors
Stephen S. Dominy,Casey C. Lynch,Florian Ermini,Malgorzata Benedyk,Agata Marczyk,Andrei Konradi,Mai Nguyen,Ursula Haditsch,Debasish Raha,Christina Griffin,Leslie J. Holsinger,Shirin Arastu-Kapur,Samer Kaba,Alexander Lee,Mark I. Ryder,Barbara Potempa,Piotr Mydel,Piotr Mydel,Annelie Hellvard,Annelie Hellvard,Karina Adamowicz,Hatice Hasturk,Hatice Hasturk,Glenn D Walker,Eric C. Reynolds,Richard L.M. Faull,Maurice A. Curtis,Mike Dragunow,Jan Potempa,Jan Potempa +29 more
TL;DR: Gingipains from Porphyromonas gingivalis drive Alzheimer’s pathology and can be blocked with small-molecule inhibitors, suggesting that gingipain inhibitors could be valuable for treating P. gedivalis brain colonization and neurodegeneration in Alzheimer's disease.
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Microglia in Alzheimer's disease.
TL;DR: Gene expression profiles indicate multiple states of microglial activation in neurodegenerative disease settings, which might explain the disparate roles ofmicroglia in the development and progression of AD pathology.
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Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis
Celeste M. Karch,Alison Goate +1 more
TL;DR: Understanding the mechanisms underlying the association of these genes with risk for disease will provide the most meaningful targets for therapeutic development to date.
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Siglec-mediated regulation of immune cell function in disease
TL;DR: The recent advances in understanding of the roles of Siglecs in the regulation of immune cell function in infectious diseases, inflammation, neurodegeneration, autoimmune diseases and cancer are described.
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The genetic landscape of Alzheimer disease: clinical implications and perspectives
TL;DR: The potential and current limitations of molecular reclassification of AD to streamline clinical trials in drug development and biomarker studies are addressed and the implications and relevance of AD genetics in clinical diagnosis and risk prediction are addressed.
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Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease
Denise Harold,Richard Abraham,Paul Hollingworth,Rebecca Sims,Amy Gerrish,Marian L. Hamshere,Jaspreet Singh Pahwa,Valentina Moskvina,Kimberley Dowzell,Amy L. Williams,Nicola L. Jones,Charlene Thomas,Alexandra Stretton,Angharad R. Morgan,Simon Lovestone,John Powell,Petroula Proitsi,Michelle K. Lupton,Carol Brayne,David C. Rubinsztein,Michael Gill,Brian A. Lawlor,Aoibhinn Lynch,Kevin Morgan,Kristelle Brown,Peter Passmore,David Craig,Bernadette McGuinness,Stephen Todd,Clive Holmes,David M. A. Mann,A. David Smith,Seth Love,Patrick G. Kehoe,John Hardy,Simon Mead,Nick C. Fox,Martin N. Rossor,John Collinge,Wolfgang Maier,Frank Jessen,Britta Schürmann,Hendrik van den Bussche,Isabella Heuser,Johannes Kornhuber,Jens Wiltfang,Martin Dichgans,Lutz Frölich,Harald Hampel,Harald Hampel,Michael Hüll,Dan Rujescu,Alison Goate,John S. K. Kauwe,Carlos Cruchaga,Petra Nowotny,John C. Morris,Kevin Mayo,Kristel Sleegers,Karolien Bettens,Sebastiaan Engelborghs,Peter Paul De Deyn,Christine Van Broeckhoven,Gill Livingston,Nicholas Bass,Hugh Gurling,Andrew McQuillin,Rhian Gwilliam,Panagiotis Deloukas,Ammar Al-Chalabi,Christopher Shaw,Magda Tsolaki,Andrew B. Singleton,Rita Guerreiro,Thomas W. Mühleisen,Markus M. Nöthen,Susanne Moebus,Karl-Heinz Jöckel,Norman Klopp,H-Erich Wichmann,Minerva M. Carrasquillo,V. Shane Pankratz,Steven G. Younkin,Peter Holmans,Michael Conlon O'Donovan,Michael John Owen,Julie Williams +86 more
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TREM2 Variants in Alzheimer's Disease
Rita Guerreiro,Rita Guerreiro,Aleksandra Wojtas,Jose Bras,Minerva M. Carrasquillo,Ekaterina Rogaeva,Elisa Majounie,Carlos Cruchaga,Celeste Sassi,Celeste Sassi,John S. K. Kauwe,Steven G. Younkin,Lili-Naz Hazrati,John Collinge,Jennifer M. Pocock,Tammaryn Lashley,Julie Williams,Jean-Charles Lambert,Philippe Amouyel,Alison Goate,Rosa Rademakers,Kevin Morgan,John Powell,Peter St George-Hyslop,Peter St George-Hyslop,Andrew B. Singleton,John Hardy +26 more
TL;DR: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease.
Journal ArticleDOI
Variant of TREM2 associated with the risk of Alzheimer's disease
Thorlakur Jonsson,Hreinn Stefansson,Stacy Steinberg,Ingileif Jonsdottir,Palmi V. Jonsson,Jon Snaedal,Sigurbjorn Bjornsson,Johanna Huttenlocher,Allan I. Levey,James J. Lah,Dan Rujescu,Harald Hampel,Ina Giegling,Ole A. Andreassen,Knut Engedal,Ingun Ulstein,Srdjan Djurovic,Carla A. Ibrahim-Verbaas,Albert Hofman,M. Arfan Ikram,Cornelia M. van Duijn,Unnur Thorsteinsdottir,Augustine Kong,Kari Stefansson +23 more
TL;DR: These findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease and find that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer’s disease had poorer cognitive function than noncarriers.
Journal ArticleDOI
Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.
Paul Hollingworth,Denise Harold,Rebecca Sims,Amy Gerrish,Jean-Charles Lambert,Jean-Charles Lambert,Jean-Charles Lambert,Minerva M. Carrasquillo,Richard Abraham,Marian L. Hamshere,Jaspreet Singh Pahwa,Valentina Moskvina,Kimberley Dowzell,Nicola Jones,Alexandra Stretton,Charlene Thomas,Alexander Richards,Dobril Ivanov,Caroline S. Widdowson,Jade Chapman,Simon Lovestone,John Powell,Petroula Proitsi,Michelle K. Lupton,Carol Brayne,David C. Rubinsztein,Michael Gill,Brian A. Lawlor,Aoibhinn Lynch,Kristelle Brown,Peter Passmore,David Craig,Bernadette McGuinness,Stephen Todd,Clive Holmes,David M. A. Mann,A. David Smith,Helen Beaumont,Donald Warden,Gordon K. Wilcock,Seth Love,Patrick G. Kehoe,Nigel M. Hooper,Emma R L C Vardy,John Hardy,Simon Mead,Nick C. Fox,Martin N. Rossor,John Collinge,Wolfgang Maier,Frank Jessen,Eckart Rüther,Britta Schürmann,R. Heun,Heike Kölsch,Hendrik van den Bussche,Isabella Heuser,Johannes Kornhuber,Jens Wiltfang,Martin Dichgans,Lutz Frölich,Harald Hampel,John Gallacher,Michael Hüll,Dan Rujescu,Ina Giegling,Alison Goate,John S. K. Kauwe,Carlos Cruchaga,Petra Nowotny,John C. Morris,Kevin Mayo,Kristel Sleegers,Karolien Bettens,Sebastiaan Engelborghs,Peter Paul De Deyn,Christine Van Broeckhoven,Gill Livingston,Nicholas Bass,Hugh Gurling,Andrew McQuillin,Rhian Gwilliam,Panagiotis Deloukas,Ammar Al-Chalabi,Christopher Shaw,Magda Tsolaki,Andrew B. Singleton,Rita Guerreiro,Thomas W. Mühleisen,Markus M. Nöthen,Susanne Moebus,Karl-Heinz Jöckel,Norman Klopp,H.-Erich Wichmann,V. Shane Pankratz,Sigrid Botne Sando,Jan O. Aasly,Maria Barcikowska,Zbigniew K. Wszolek,Dennis W. Dickson,Neill R. Graff-Radford,Ronald C. Petersen,Cornelia M. van Duijn,Monique M.B. Breteler,M. Arfan Ikram,Anita L. DeStefano,Annette L. Fitzpatrick,Oscar L. Lopez,Lenore J. Launer,Sudha Seshadri,Claudine Berr,Dominique Campion,Jacques Epelbaum,Jean-François Dartigues,Christophe Tzourio,Annick Alpérovitch,Mark Lathrop,T. Feulner,Patricia Friedrich,Caterina Riehle,Michael Krawczak,Stefan Schreiber,Manuel Mayhaus,S. Nicolhaus,Stefan Wagenpfeil,Stacy Steinberg,Hreinn Stefansson,Kari Stefansson,Jon Snaedal,Sigurbjorn Bjornsson,Palmi V. Jonsson,Vincent Chouraki,Vincent Chouraki,Vincent Chouraki,Benjamin Genier-Boley,Benjamin Genier-Boley,Benjamin Genier-Boley,Mikko Hiltunen,Hilkka Soininen,Onofre Combarros,Diana Zelenika,Marc Delepine,María J. Bullido,Florence Pasquier,Ignacio Mateo,Ana Frank-García,Elisa Porcellini,Olivier Hanon,Eliecer Coto,Victoria Alvarez,Paolo Bosco,Gabriele Siciliano,Michelangelo Mancuso,Francesco Panza,Vincenzo Solfrizzi,Benedetta Nacmias,Sandro Sorbi,Paola Bossù,Paola Piccardi,Beatrice Arosio,Giorgio Annoni,Davide Seripa,Alberto Pilotto,Elio Scarpini,Daniela Galimberti,Alexis Brice,Didier Hannequin,Federico Licastro,Lesley Jones,Peter Holmans,Thorlakur Jonsson,Matthias Riemenschneider,Kevin Morgan,Steven G. Younkin,Michael John Owen,Michael Conlon O'Donovan,Philippe Amouyel,Julie Williams +177 more
TL;DR: Meta-analyses of all data provided compelling evidence that ABCA7 and the MS4A gene cluster are new Alzheimer's disease susceptibility loci and independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance.
Journal ArticleDOI
Genome-wide association study indentifies variants at CLU and CR1 associated with Alzheimer’s disease
J-C Lambert,Simon Heath,G Even,Dominique Campion,K. Sleegers,Mikko Hiltunen,O Cambarros,Diana Zelenika,María J. Bullido,Béatrice Tavernier,Luc Letenneur,Karolien Bettens,Claudine Berr,Florence Pasquier,Nathalie Fievet,P Barbager-Gateau,S. Engelborghs,P.P. De Deyn,Ignacio Mateo,A Franck,Seppo Helisalmi,Elisa Porcellini,Olivier Hanon,M de Pancorbo,Corinne Lendon,Carole Dufouil,C Jaillard,Thierry Léveillard,Alvarez,Paolo Bosco,Michelangelo Mancuso,Francesco Panza,Benedetta Nacmias,Paola Bossù,Paola Piccardi,Giorgio Annoni,Davide Seripa,Daniela Galimberti,Didier Hannequin,Federico Licastro,Hilkka Soininen,Karen Ritchie,Hélène Blanché,J. F. Dartigues,Christophe Tzourio,Ivo Gut,Christine Van Broeckhoven,Annick Alpérovitch,P. Amouyel +48 more
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