Дисертації з теми "Beta-Amyloid peptides"
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Kadlčík, Vojtěch. "Oxidation of beta-amyloid and model peptides." Paris 11, 2006. http://www.theses.fr/2006PA112008.
The goal of my thesis work was to characterize oxidation products of beta-amyloid peptide (Abeta), which is implied in the development of Alzheimer's disease. To study the effect of peptide structure on the redox processes, oxidation properties of Abeta(1-40) were compared to the peptide with reverse sequence, Abeta(40-1). Azide and hydroxyl radicals used for oxidation were produced by gamma radiolysis. Final products were characterized by a variety of analytical techniques (HPLC, GC, MALDI-TOF MS, fluorescence and raman spectrometry). To establish the role of peptide environment on its redox properties, oxidation was carried out in three different systems: homogeneous aqueous solution, micellar system (SDS) and in the presence of phospholipids vesicles (POPC). In homogeneous aqueous solution, oxidation products are different for both peptides. The main oxidation targets are Met35 for Abeta(1-40) and Tyr10 for Abeta(40-1). The presence of micelles and phospholipid vesicles has an important impact on the oxidation pathways. These changes could be related to changes in peptide conformations studied by circular dichroism. We have also shown that Abeta degradation products may catalytically induce alternation of phospholipids. This process is initiated by reaction of hydrogen radicals with the peptide. Our results are interesting in the context of the development of Alzheimer's disease as they may bring an insight into the role of Abeta(1-40) interaction with phospholipids membrane for the redox properties of the peptide
Tanase, Maria Elena. "Nanomaterials self-assembly driven by beta-amyloid peptides." ScholarWorks@UNO, 2005. http://louisdl.louislibraries.org/u?/NOD,223.
Title from electronic submission form. "A thesis ... in partial fulfillment of the requirements for the degree of Master of Science in the Department of Chemistry"--Thesis t.p. Vita. Includes bibliographical references.
Chen, Zhongjing. "NMR structural characterization of beta-amyloid peptides and their inhibitors." [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=973392266.
Kittner, Madeleine. "Folding and aggregation of amyloid peptides." Phd thesis, Universität Potsdam, 2011. http://opus.kobv.de/ubp/volltexte/2011/5357/.
Die Aggregation des Amyloid β (Aβ) Peptids zu Amyloidfibrillen wird mit dem Ausbruch der Alzheimer Krankheit in Verbindung gebracht. Die toxische Wirkung auf Zellen wird vor allem den zeitigen Intermediaten in Form von löslichen Oligomeren zugeschrieben. Aufgrund deren ungeordneter und flüchtiger Natur kann die molekulare Struktur solcher zeitigen Oligomere oft experimentell nicht aufgelöst werden. In der vorliegenden Arbeit wurden aufwendige atomistische Replica-Exchange-Molekulardynamik-Simulationen durchgeführt, um die molekulare Struktur von Monomeren und Oligomeren der Fragmente Aβ(25-35) und Aβ(10-35)-NH2 in Wasser zu untersuchen. Die Faltung und Aggregation von Aβ(25-35) wurde bei neutralem pH und 293 K untersucht. Monomere dieses Fragments bilden hauptsächlich β-Haarnadelkonformationen im Gleichgewicht mit Knäulstrukturen. Innerhalb der β-Haarnadelkonformationen bilden die Residuen G29 und A30 einen β-turn, während N27–K28 and I31–I32 ein β-Faltblatt bilden. Diese β-Haarnadelkonformationen bildeten den Ausgangspunkt zur Modellierung spontaner Aggregation. Wie zu erwarten, bilden sich eine Vielzahl verschiedener, gering besetzter Dimer- und Trimerkonformationen. Mit Hilfe einer gröberen Einteilung können diese in ungeordnete und fibrillähnliche Oligomere unterteilt werden. Ungeordnete Oligomere bilden kompakte Strukturen, die nur durch wenige intermolekulare Wasserstoffbrückenbindungen (HBB) stabilisiert sind. Typisch für fibrillähnliche Oligomere ist hingegen die Ausbildung großer intermolekularer β-Faltblätter. In vielen dieser Oligomere finden wir antiparallele, in- oder out-of-register β-Faltblätter gebildet durch vollständig ausgestreckte Peptide. Ein kleiner Teil der fibrillähnlichen Trimere bildet parallele, V-förmige β-Faltblätter. Die Ausdehnungen ausgestreckter und V-förmiger Oligomere entspricht in etwa den Durchmessern von zwei verschiedenen, experimentell gefundenen Fibrillmorphologien für Aβ(25-35). Die Umwandlung von ungeordneten zu fibrillähnlichen Aβ(25-35) Dimeren ist energetisch begünstigt, läuft aber nicht freiwillig ab. Fibrillähnliche Dimere haben eine geringere Energie aufgrund günstiger Peptidwechselwirkungen (HBB, Salzbrücken), welche durch den Verlust an Entropie kompensiert wird. Etwa 25 % entsprechen dem Verlust an Konfigurationsentropie. Der restliche Anteil wird einem Verlust an Lösungsmittelentropie aufgrund von hydrophoben und elektrostatischen Effekten zugesprochen. Im Gegensatz zur Umwandlung in fibrillähnliche Dimere, ist die Assoziation von Monomeren oder Oligomeren entropisch begünstigt. Beim Vergleich thermodynamischer Eigenschaften der Monomer-, Dimer- und Trimersysteme zeigt sich im Verlauf der Aggregation, wie erwartet, eine Abnahme der Konfigurationsentropie. Zusätzlich nimmt die dem Lösungsmittel zugängliche Oberfläche (SASA), insbesondere die hydrophobe SASA, ab. In Verbindung damit beobachten wir eine Abnahme der freien Solvatisierungsenergie, welche den Verlust an Konfigurationsentropie kompensiert. Mit anderen Worten, der hydrophobe Effekt in Kombination mit elektrostatischen Wechselwirkungen führt zu einem Ansteigen der Lösungsmittelentropie und begünstigt damit die Aggegation. Die spontane Faltung des Aβ(10-35)-NH2 Monomers wurde für zwei verschiedene Proteinkraftfelder, GROMOS96 43a1 und OPLS/AA, untersucht und mit primären NMR-Daten aus der Literatur, gemessen bei pH 5.6 und 283 K, verglichen. Beide Kraftfelder generieren unterschiedliche Hauptkonformationen. Der Vergleich zwischen experimentellen und berechneten Kern-Overhauser-Effekt (NOE) Abständen ist nicht ausreichend, um zwischen beiden Kraftfeldern zu unterscheiden. Der Vergleich mit Kopplungskonstanten aus Experiment und Simulation zeigt, dass beide Simulationen einem pH-Wert geringer als 5.6 ensprechen. Basierend auf den bisherigen Ergebnissen können wir nicht entscheiden, welches Kraftfeld eine bessere Beschreibung für dieses System liefert. Die Dimerisierung von Aβ(10-35)-NH2 wurde bei neutralem pH und 300 K untersucht. Wir finden eine Vielzahl verschiedener, gering besetzter Dimerstrukturen, welche eher durch Seitenkettenkontakte als durch spezifische HBB stabilisiert sind. Wie bei den Aβ(25-35) Dimeren, ist die Umwandlung zu β-Faltblattreichen, fibrillähnlichen Aβ(10-35) Dimeren energetisch begünstigt, konkurriert aber mit einem Entropieverlust. Die Umwandlung wird in diesem Fall durch elektrostatische Wechselwirkungen zwischen Peptid und Lösungsmittel und innerhalb des Lösungsmittels bestimmt.
Davison, Catherine J. "The interactions of the C-terminus of acetlycholinesterase with amyloid-beta peptides." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.496845.
Tang, Christian C. "Structure and Activity of Metallo-Peptides." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6961.
Mishra, Pamela Haradhan. "Unbinding of abeta peptides from amyloid fibrils explicit solvent molecular dynamics study /." Fairfax, VA : George Mason University, 2008. http://hdl.handle.net/1920/3419.
Vita: p. 48. Thesis director: Dmitri Klimov. Submitted in partial fulfillment of the requirements for the degree of Master of Science in Bioinformatics and Computational Biology. Title from PDF t.p. (viewed Mar. 17, 2009). Includes bibliographical references (p. 45-47). Also issued in print.
Mikkonen, Saara. "Electrophoretic focusing in microchannels combined with mass spectrometry : Applications on amyloid beta peptides." Doctoral thesis, KTH, Tillämpad fysikalisk kemi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-193134.
QC 20160930
Zhang, Qishan, and 张绮珊. "Investigating biological mechanisms for the induction of autophagy in neurons stressed by beta-amyloid peptides." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hdl.handle.net/10722/193067.
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Anatomy
Doctoral
Doctor of Philosophy
Bautista, Mahealani Roberts. "Identification and design of small molecules that associate with aggregated Alzheimer's-related beta-amyloid peptides." Diss., [La Jolla, Calif.] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p3344755.
Title from first page of PDF file (viewed Apr. 3, 2009). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 178-202).
SIRONI, ERIKA. "Nuclear Magnetic Resonance characterization of Beta-amyloid peptides and their interactions with anti-amyloidogenic compounds." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2013. http://hdl.handle.net/10281/41573.
Wang, Feng. "Interaction between pancreatic cancer and beta cells : intraislet significance of islet amyloid polypeptide /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-3300-6/.
Lai, Yinzhi. "CPLA2 key enzyme for astrocytic cell membrane phase property change induced by abeta /." Diss., Columbia, Mo. : University of Missouri-Columbia, 2007. http://hdl.handle.net/10355/5992.
The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on April 14, 2008) Includes bibliographical references.
Fioravanzo, Lara. "Study of role of A-Beta peptides on angiogenesis related to Alzheimer's disease." Doctoral thesis, Università degli studi di Padova, 2009. http://hdl.handle.net/11577/3426012.
Uno dei principali impedimenti alla ricostruzione di tessuti ed organi nell'ingegneria tessutale è la mancanza di strategie che assicurino costante e stabile vascolarizzazione. L'acquisizione di nuove conoscenze sui meccanismi che intervengono nel processo angiogenico potrebbe permettere una efficace applicazione clinica nella ricostruzione di tessuti e organi da una parte e nella riduzione della eccessiva crescita vascolare in patologie angiogenesi-dipendente dall'altra. L'angiogenesi è un processo complesso in cui numerosi cellule e mediatori cellulari interagiscono per stabilire un microambiente specifico per la crescita di nuovi vasi sanguigni (Bouïs et al, 2006). Questo processo si verifica sia in condizioni fisiologiche (sviluppo embrionale, ciclo mestruale, gravidanza, guarigione di ferite) che patologiche (processi infiammatori, psoriasi, crescita di metastasi). Negli ultimi tempi si sta affermando l'ipotesi che la demenza di Alzheimer (AD) non sia solamente una malattia neurodegenerativa caratterizzata da degenerazione neuronale e perdita delle connessioni sinaptiche ma anche una patologia vascolare. Numerose infatti sono le alterazioni riscontrabili a livello dei capillari cerebrali nei soggetti AD: vasocostrizione dei microvasi cerebrali, degenerazione delle cellule muscolari lisce vasali e alterazione della membrana basale. In particolare desta vasto interesse il possibile legame tra angiogenesi e AD derivante dall'osservazione di una aumentata densità vascolare in prossimità delle placche senili nei pazienti AD rispetto a soggetti anziani non dementi (Vagnucci and Li, 2003). Le placche senili, depositi extracellulari e vascolari di materiale proteico costituite in prevalenza dal peptide β-amiloide (Aβ), assieme ai grovigli neurofibrillari (NFT), costituiti dalla forma iperfosforilata della proteina τ, rappresentano le principali alterazioni neuro-patologiche riscontrabili nel cervello di soggetti AD (Robertson et al., 2003). Numerosi studi in vivo, ex-vivo e in vitro riportano risultati contraddittori sulla capacità del peptide Aβ di stimolare il processo angiogenico (Paris et al., 2004; Cantara et al., 2004). Scopo di questo lavoro di ricerca è il tentativo di comprendere alcuni meccanismi che favoriscono questo processo. Da questo lavoro di ricerca è emerso che il peptide Aβ è pro-angiogenico in vivo, ex-vivo e in vitro su cellule endoteliali cerebrali umane e anti-angiogenico su cellule endoteliali cerebrali di ratto, probabilmente come conseguenza dell'effetto citotossico effettuato dal peptide su queste ultime. Inoltre il Aβ1-42 non interferisce sulla via di espressione e rilascio di VEGF da parte di cellule endoteliali cerebrali e di astrociti di ippocampo di ratto in coltura. Gli astrociti secernono sostanze che inducono angiogenesi e rilascio di IL-6 da parte delle cellule endoteliali cerebrali di ratto in coltura indipendentemente dal trattamento con Aβ1-42. Infine la presenza di hVEGF165 inibisce l'effetto tossico e anti-angiogenico del peptide probabilmente in seguito al sequestramento del Aβ1-42 ad opera del legame Aβ1-42-hVEGF165. Altri studi sono necessari al fine di comprendere i meccanismi di angiogenesi correlata con la AD sebbene sembri evidente che essa possa derivare dall'interazione di diversi tipi cellulari in risposta all'effetto del peptide Aβ su di esse. Sembra tuttavia che l'alterazione dell'endotelio capillare e la conseguente ipossia contribuiscano all'attivazione di tale processo.
Puig, Gomà-Camps Eduard. "Structural characterization of amyloid beta oligomers with functional links associated to Alzheimer's disease." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/667258.
La malaltia d'Alzheimer (AD) és la forma més comuna de demència. Va ser descrita per primera vegada el 1906 per Alois Alzheimer. Més endavant, al 1984, George Glenner i Colin Masters van aïllar el pèptid amiloide-beta (Aβ) d'un cervell humà i el van associar a la malaltia. Des de llavors, la hipòtesi amiloide ha estat un tema bastant controvertit discutit entre la comunitat científica. Una possible explicació és l’alta complexitat del sistema a causa de la varietat de formes d’agregació que Aβ pot adoptar. Per tant, entendre els vincles entre l'agregació de proteïnes i la neurotoxicitat, i especialment l'obtenció de les estructures 3D dels agregats responsables de la neurotoxicitat, és clau per dissenyar estratègies diagnòstiques i terapèutiques efectives. Malauradament, aquest tema continua sent un dels problemes pendents més importants. El grup de la Dra. Carulla ha estat treballant en la hipòtesi que l'Aβ interactua amb la membrana cel·lular que condueix a una deshomeostasi iònica. Per estudiar aquest escenari, el grup ha canviat el paradigma i ha tractat Aβ com a proteïna de membrana i aplicant tècniques biofísiques ben establertes per a caracteritzar proteïnes de membrana per tal d’estudiar Aβ. D'aquesta manera, el grup ha demostrat que Aβ és capaç de formar un tipus d'oligòmers en presència de micel·les de detergent que adopten una estructura molt específica i definida amb capacitat de formar porus a través de membranes lipídiques. Es refereixen a aquest tipus d’oligòmers com a oligòmers formadors de porus barril β (βPFO). A la present tesi doctoral, presentem l’estudi realitzat per identificar mitjançant diferents tècniques biofísiques, l'estructura 3D de βPFO. Hem utilitzat detergents per estudiar el procés d’oligomerització en un entorn mimètic de membrana. Les micel·les en comparació amb altres entorns biomimètics basats en lípids, permeten l'aplicació d’estratègies d'espectrometria de masses (MS) i de ressonància magnètica nuclear (RMN) ben establertes, proporcionant així informació estructural d'alta resolució. Atès que l’acumulació de diferents quantitats d’Aβ a la membrana és un escenari plausible en el context de la malaltia, hem utilitzat diferents relacions de micel·les Aβ a detergents ([Aβ]: [M]) per estudiar el paper d’aquesta variable en l’oligomerització. procés d'Aβ.
Mirats, Arce Andrea. "Computational study of the properties of cu-peptide complexes relevant to alzheimer’s diseases." Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/400088.
Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive and memory impairment. One of its main hallmarks is the presence of extracellular deposits of the amyloid-beta peptide (Aß), in which metal cations have been shown to play an important role. In particular, the interaction of the redox active Cu2+ metal cation with Aβ has been found to interfere in amyloid aggregation and to lead to reactive oxygen species (ROS). Thus, a detailed knowledge of the structure of Cu-Aß1-16 complexes is essential to get a better understanding of this critical process. In the last decade many conflicting coordination spheres on the Cu2+-Aß complexes have been proposed, but the structure of these complexes is still disputed and highly pH dependent. The present thesis is structured in seven chapters. Chapter 1 introduces the AD framework in which the thesis is located, pointing out the importance of the presence of metal ions in the Aß deposits and its role in the ROS formation, as well as the most relevant treatments used until now. Then, Chapter 2 introduces the goals that this thesis aims. After that, Chapter 3 overviews the general theoretical aspects behind it, such as electronic structure with quantum mechanics or molecular mechanics and molecular dynamics methods, as well as homology modeling technics. However, the computational details are described in each results topic, which encloses four chapters. The first one, Chapter 4, presents the building and characterization of the 3D structure of Cu2+-Aß1-16 complexes. In the next chapter, Chapter 5, the study of the Cu+-Aß1-16 species obtained by reduction of Cu2+-Aß1-16 complexes from the last chapter along with the redox properties of this couple, as well as the stability of these species, is reported. Then, Chapter 6 investigates the role of these species in the catalytic cycle of the H2O2 formation; specially, the O2 activation in order to obtain the superoxide specie. Lastly, some peptides are studied as Cu chelates as possible AD treatment in Chapter 7. Finally, Chapter 8 addresses general conclusions of the present thesis. Moreover, there is a reference section with all the references cited in this thesis, as well as Appendix parts that support the information given in Chapters 4 to 7.
Padayachee, Eden Rebecca. "Neuronal nitric oxide synthase : a biomarker for Alzheimers disease : interaction of neuronal nitric oxide synthase with beta-amyloid peptides in the brain." Thesis, Rhodes University, 2011. http://hdl.handle.net/10962/d1007677.
Martineau, Eric. "Modeling Peptide-binding Interactions and Polymer-binding Interactions and their Role in Mass Spectrometry." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/24197.
Vukic, Vanja. "The expression of inflammatory genes in human brain endothelial cells stimulated by beta-amyloid peptides is mediated by JNK-AP1 signaling pathway." Thesis, University of Ottawa (Canada), 2008. http://hdl.handle.net/10393/27740.
Vilaprinyó, Pascual Sílvia. "The dynamic nature of amyloid-beta protein aggregation and its association to Alzheimer’s disease." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/305364.
La proteïna beta amiloide (Aß) es troba estretament lligada a la malaltia d’Alzheimer (MA). Tot i el seu rol central en la malaltia, Aß es produeix de forma regular en humans sans. És el processament aberrant de la proteïna que en determina la seva acumulació i agregació, primer en intermedis oligomèrics transitoris que evolucionen cap a les estructures fibril·lars que composen les plaques amiloides dipositades al cervell dels malalts de la MA. La neurotoxicitat associada a la malaltia s’atribueix a les espècies intermèdies, per bé que se’n desconeix l’estequiometria i l’estructura. En la present tesi doctoral, hem determinat l’estequiometria i l’estructura dels oligòmers d’Aß formats en els estadiatges inicials de l’agregació. Hem provat que aquests oligòmers mostren neurotoxicitat en cultius neuronals primaris. Addicionalment, hem demostrat que el clàssic anàlisi per electroforesi en gel proporciona resultats confusos a l’hora de determinar l’estequiometria dels oligòmers. Els resultats presentats en la tesi doctoral també mostren evidències de que les fibres amiloides d’Aß es troben en equilibri amb monòmers i oligòmers de baix pes molecular. Aquest equilibri ha demostrat ser dependent de les propietats fisicoquímiques de les pròpies fibres d’Aß.
Itkin, Anna. "Etude pluridisciplinaire de peptides liés à la maladie d'Alzheimer: de la protéine précurseur de l'amyloïde (APP) aux oligomères de beta-amyloïde et aux inhibiteurs de gamma-sécrétase." Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209705.
Les propriétés conformationnelles du segment transmembranaire (TM) de l’APP peuvent affecter sa protéolyse par la γ-sécrétase. Ces propriétés ne sont pas encore clairement établies. Afin de comprendre le rôle des variations structurelles du TM dans le traitement de l'APP, des détails structurels des peptides APP_TM4K, chimiquement synthétisés, ont été étudiés dans la bicouche lipidique en utilisant la réflexion totale atténuée par spectroscopie infrarouge à transformée de Fourier (ATR-FTIR) et la résonance magnétique nucléaire à l’état solide (ssNMR). Tandis que la structure secondaire globale du peptide APP_TM4K est hélicoidale, une hétérogénéité conformationnelle et orientée a été observée pour le site de clivage γ et, dans une plus faible mesure, pour le site de clivage ζ. Ces variabilités conformationnelles autour des sites de clivage γ et ζ peuvent avoir des implications importantes dans le mécanisme de clivage et donc dans la production d’Aβ. Il a été aussi démontré que la dernière glycine dans le motif de dimérisation GxxxG est transmembranaire. Ceci peut impliquer que la dimérisation via ce motif pourrait servir d’ancrage et conférer une orientation transmembranaire stable au segment transmembranaire de l’APP.
Le peptide amyloïde β est directement lié à la maladie d’Alzheimer. Partant de sa forme monomérique, l’Aβ s'agrège pour produire en final des fibrilles et aussi de manière transitoire toute une gamme d'oligomères, ces derniers étant la plupart neurotoxiques. Une dérégulation de l’homéostasie du Ca2+ dans le cerveau vieillissant et dans des troubles neurodégénératifs joue un rôle crucial dans de nombreux processus et contribue au dysfonctionnement et à la mort cellulaire. Nous avons postulé que le calcium peut permettre ou accélérer l'accumulation d'Aβ. Le modèle d'accumulation d'Aβ (1-40) et celui d'Aβ (1-40) E22G, un peptide amyloïde portant la mutation arctique qui cause une apparition prématurée de la maladie, ont été comparé. Nous avons constaté qu'en présence de Ca2+, l’Aβ (1-40) forme de préférence des oligomères semblables à ceux formés par l’Aβ (1-40) E22G avec ou sans Ca2+, tandis qu'en absence de Ca2+ l'Aβ (1-40) s’agrège sous forme de fibrilles. Les ressemblances morphologiques entre oligomères ont été confirmées par microscopie de force atomique. La distribution des oligomères et des fibrilles dans des échantillons différents a été détectée par électrophorèse sur gel suivie d’une analyse par Western blot, dont les résultats ont été confirmés par des expériences de fluorescence à la thioflavine T. Dans les échantillons sans Ca2+, l’ATR-FTIR révèle la conversion des oligomères en feuillets β antiparallèles en la conformation caractéristique des fibrilles en feuillets β parallèles. En général, ces résultats nous ont ameré à conclure que les ions calcium stimulent la formation d'oligomères d'Aβ (1-40), qui sont impliqués dans la pathogénèse d'AD.
Malgré les progrès énormes obtenus dans la compréhension de la maladie (AD), il reste un défi majeur, celui du développement de médicaments nouveaux et efficaces. Afin d’obtenir des éclaircissements sur le mécanisme d'action de deux nouveaux puissants modulateurs de la γ-sécrétase - le benzyl-carprofen et le sulfonyl-carprofen dans la bicouche lipidique, la technique de RMN à l’état solide a été employée. Précédemment, les dérivés du carprofen ont été localisés dans des membranes de lipides par des expériences de diffusion (scattering) des neutrons. Les contraintes déterminées à partir des expériences de ssNMR ont permis d’affiner leurs positions et d’obtenir une orientation précise dans la double couche lipidique. Ces résultats combinés indiquent que le mécanisme probable de modulation du clivage par la γ-sécrétase est une interaction directe des carprofènes avec le domaine TM de l’APP. Une telle interaction, empêcherait à la formation de dimères d'APP, dimérisation nécessaire au clivage séquentiel par la γ-sécrétase, diminuant ou réduisant ainsi énormément la production d’Aβ, tout particulièrement d’Aβ42.
Les résultats de ce travail apporte de nouvelles informations sur les processus clés impliqués dans l'AD; Production de l'Aβ à partir de l'APP, formation des oligomères d'Aβ et mécanisme d'action potentiel de molécules thérapeutiques. Nous pensons que ces résultats pourront permettre une meilleure compréhension de la maladie et pourront aider dans la conception de nouveaux médicaments contre cette maladie.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. There is no cure and the disease is fatal. One of the characteristic histopathological markers of AD is the presence of proteinaceous deposits, amyloid plaques, in the brain. These plaques are formed by the amyloid β-peptides (Aβ) 40- and 42-residue-long, which are protease cleavage products of the amyloid precursor protein (APP). Elucidation of some of the key processes in the cause and the development of AD is crucial for the development of new and efficient treatments.
Conformational properties of the transmembrane (TM) segment of APP may affect its proteolytic processing by γ-secretase. These properties have not been definitely established. In addressing the role of structural variations of the TM sequence in APP processing, structural details of the chemically synthesized APP_TM4K peptides within the membrane bilayers were studied using Attenuated total reflection Fourier transform spectroscopy (ATR-FTIR) and solid-state nuclear magnetic resonance (ssNMR) techniques. While the overall secondary structure of the APP_TM4K peptide is an α-helix, conformational and orientational heterogeneity was observed for the γ-cleavage site and, to a smaller extent, for the ζ-cleavage site. Evidence for the conformational variability around γ- and ζ-cleavage sites may have important implications for the cleavage mechanism and hence for the Aβ production. It was also found that the last glycine within the sequence of GxxxG motifs is in the transmembrane orientation, implying that dimerization via these motifs may act as an anchor, confining the TM dimer to the stable transmembrane orientation.
Amyloid β-peptide is directly linked to AD. Starting from its monomeric form, Aβ aggregates into fibrils and / or oligomers, the latter being the most neurotoxic. Dysregulation of Ca2+ homeostasis in aging brains and in neurodegenerative disorders plays a crucial role in numerous processes and contributes to cell dysfunction and death. Here we postulated that calcium may enable or accelerate the aggregation of Aβ. The aggregation pattern of Aβ(1-40) and of Aβ(1-40)E22G, an amyloid peptide carrying the Arctic mutation that causes early onset of the disease, were compared. We found that in the presence of Ca2+, Aβ(1-40) preferentially formed oligomers similar to those formed by Aβ(1-40)E22G with or without added Ca2+, whereas in the absence of added Ca2+ the Aβ(1-40) aggregated to form fibrils. Morphological similarities of the oligomers were confirmed by contact mode atomic force microscopy (AFM) imaging. The distribution of oligomeric and fibrillar species in different samples was detected by gel electrophoresis and Western blot analysis, the results which were further supported by thioflavin T fluorescence experiments. In the samples without Ca2+, Fourier transform infrared spectroscopy revealed conversion of oligomers from an anti-parallel β-sheet to the parallel β-sheet conformation characteristic of fibrils. Overall, these results led us to conclude that calcium ions stimulate the formation of oligomers of Aβ(1-40), that have been implicated in the pathogenesis of AD.
Despite the tremendous progress in understanding AD, there remains the challenge of the development of new and efficient drugs. In order to shed light onto the mechanism of action of two new potent γ-secretase modulators -- benzyl-carprofen and sulfonyl-carprofen within lipid bilayers, ssNMR technique was employed. Using neutron scattering experiments it was previously found that sulfonyl-carprofen and benzyl-carprofen partition into the headgroup region of the lipid bilayer. The orientational constraints derived from the ssNMR experiments refined their position into precise orientation. Combined, these results indicate that carprofen-derivatives can directly interact with the region of APP that mediates dimerization. Such interaction, would interfere with proper APP-dimer formation, which is necessary for the sequential cleavage by γ-secretase, diminishing or greatly reducing Aβ42 production.
Results obtained during this work shed new light onto some of the key processes in AD: Aβ production from APP, formation of Aβ oligomers and insights into the mechanism of action of potential therapeutics. We believe that these results will promote a better understanding of the disease and will help in future drug design.
Doctorat en Sciences
info:eu-repo/semantics/nonPublished
Younan, Nadine D. "The influence of copper (II) ions on the structure and stability of the prion protein and its interaction with the amyloid-beta peptides." Thesis, Queen Mary, University of London, 2012. http://qmro.qmul.ac.uk/xmlui/handle/123456789/2510.
Krabbe, Grietje [Verfasser]. "Microglial properties in health and disease : modulation of microglial phagocytic activity and migration by monoamine neurotransmitters or presence of amyloid beta peptides / Grietje Krabbe." Berlin : Freie Universität Berlin, 2011. http://d-nb.info/1026266033/34.
Py, Nathalie. "Métalloprotéases matricielles et maladie d'Alzheimer : étude du rôle de MT1-MMP dans le métabolisme de l'APP/Aß." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5073.
We investigate the role of matrix metalloproteinases in the metabolism of beta amyloid peptide (Abeta) and its amyloid precursor protein (APP) in Alzheimer's disease (AD). Our results in the 5xFAD mouse model of AD indicate a cell-type and age-dependent upregulation of MMP-2 -and MT1-MMP active forms. This is concomitant with the increase of toxic forms of Abeta, but also of cytotoxic C99, a membrane fragment of APP generated by beta-secretase and that gives rise to Abeta after gamma-secretase cleavage. We show in HEK cells overproducing Abeta that while MT1-MMP interacts with APP and boosts C99 and Abeta production, MMP-2 does not interact with APP and degrades Abeta. These results uncover a MMP-specific regulatory crosstalk with amyloid and also MT1-MMP as a new pro-amyloidogenic proteinase. We want now to gain further insight into the mechanisms that support MT1-MMP effects, namely the possible modulation by MT1-MMP of beta- and gamma-secretase activities and/or APP trafficking
Ninot, Pedrosa Martí. "Towards the validation of a druggable amyloid-beta oligomer as a target for Alzheimer´s disease = Cap a la validació d’un oligomer de beta-amiloide com a diana en la malaltia d’Alzheimer." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/565537.
Itkin, Anna. "Multidisniplinary study of Alzheimer's disease-related peptides : from amyloid precursor protein (APP) to amyloid β-oligomers and γ-secretase modulators". Thesis, Strasbourg, 2012. http://www.theses.fr/2012STRAF051/document.
A histopathological characteristic of Alzheimer’s disease (AD) is the presence of amyloid plaques formed by amyloid β(A) peptides of 40 and 42 residues-long, which are the cleavage products of APP by proteases. To understand the role of structural changes in the TM domain of APP, APP_TM4K peptides were studied in the lipid bilayer using ATR-FTIR and ssNMR. While the overall secondary structure of the APP_TM4K peptide is helical, conformational and orientational heterogeneity was observed for the y- and for the -cleavage sites, which may have implications for the cleavage mechanism and therefore the production of Aβ. Starting from its monomeric form, Aβ peptides aggregate into fibrils and / or oligomers, the latter being the most neurotoxic. We found that in the presence of Ca2 +, Aβ (1-40) preferably forms oligomers, whereas in the absence of a2 + Aβ (1-40) aggregates into fibrils. In samples without Ca2 +, ATR-FTIR shows conversion from antiparallel β sheet conformation of oligomers into parallel β sheets, characteristic of fibrils. These results led us to conclude that Ca2 +stimulates the formation of oligomers of Aβ (1-40), that have been implicated in the pathogenesis of AD. Position and precise orientation of two new drugs powerful modulators of γ-secretase benzyl-carprofen and carprofen sulfonyl in the lipid bilayer were obtained from neutron scattering and ssNMR experiments. These results indicate that carprofen-derivatives can directly interact with APP. Such interaction would interfere with proper APP-dimer formation, which is necessary for the sequential cleavage by β -secretase, diminishing or greatly reducing Aβ42 production
Melo, Thaiany Quevedo. "Análise da expressão das proteínas Rab anterior à agregação proteica associada a neurodegeneração." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/5/5160/tde-10082012-122654/.
Neurodegeneration is a process that leads to progressive cell death. The anterograde and retrograde neuronal traffic as well as the traffic between compartments are essential for cell viability. The Rab proteins belong to the small GTPases family with function of vesicles and organelle trafficking. Rab proteins can recruit motor proteins such as KIF 1B and KIF 5 that are responsible for anterograde mitochondrial transport. The association of intracellular traffic disturb with neurodegenerative diseases have been theme of recent studies. Thereat the objective of this study is analyze the expression of Rab and motor proteins that can contribute for the understanding about the disturb of the intracellular traffic that precedes protein aggregation involved in neurodegeneration. For this purpose it was employed the model of rotenone treatment for induction of aggregation in aged Lewis rats that were exposed to rotenone during 4 weeks in order to evaluate Rabs expression. The levels of motor proteins KIF 1B and KIF 5 expression were evaluated before and during the formation of protein aggregates in hippocampus, substantia nigra and locus coeruleus cell cultures of neonates Lewis rats, exposed to rotenone for 24 hours or 48 hours in the concentrations of 0.1nM, 0.3nM or 0.5nM. It was observed decreased levels of Rab 1 expression in hippocampus and locus coeruleus. Rabs 4,5 and 6 were increased in the hippocampus, but in the substantia nigra the expression of Rab 1 increased and Rab 6 decreased. In the locus coeruleus the Rab 6 increased, but Rabs 1, 5 and 11 decreased. The expression of KIF 5 increased after 0.1nM of rotenone and decreased after the exposure to 0.5nM of for 48 hours in cultured cell from the locus coeruleus. In the substantia nigra the KIF1B and KIF 5 increased after treatment with 0.5nM for 48 hours in vitro, but these protein decreased after treatment with 0.3nM for 24 hours in vitro, and KIF 5 after treatment with 0.1nM for 48 hours. These results allow us conclude that the expression of important proteins for the mitochondrial and vesicles traffic are altered and participate of intracellular events that precede the neurodegeneration
Danielsson, Jens. "NMR studies of the amyloid beta-peptide." Doctoral thesis, Stockholm University, Department of Biochemistry and Biophysics, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-1410.
The Amyloid beta peptide (Ab) is related to Alzheimer’s disease and is suggested to be the molecular pathogenic species of the disease, probably through the neurotoxic effect of Ab oligomers. Here the results from biophysical studies of Ab and fragments thereof, are presented. Pulsed field gradient NMR diffusion experiments show that Ab exists mainly as an unfolded monomer. In addition, the hydrodynamic radius of Ab suggests that Ab has residual secondary structure propensities. CD experiments reveal that Ab has a high propensity to adopt a polyproline type II (PII) helix at low temperature. NMR diffusion measurements as well as the 3JHNH values show that increasing the temperature from 4 C induces a structure transition from PII propensity to a beta strand propensity around 15 C and to a random coil conformation at higher temperature. The small hydrodynamic radius at low temperature may be explained by the presence of a population of a hairpin conformation as was suggested by MD simulations. 15N relaxation and secondary chemical shifts suggest that Ab consists of 6 structural regions, two regions with high PII propensity are separated by a highly mobile region located in the N-terminal part of the peptide. In the C-terminal part two regions with a propensity to adopt b-strand are located, separated by a mobile region. The structural propensities of soluble monomeric Ab agree well with the structure of the peptide in fibril aggregates as well as in SDS micelles. Ab binds zinc specifically and with high affinity. This interaction was studied using heteronuclear correlation experiments. The metal ligands were determined to be three histidines, 6,13 and 14 and the N-terminus. The Ab peptide also binds b-cyclodextrin and the combined use of NMR diffusion experiments and induced chemical shifts show that Ab has at least two binding sites for b-cyclodextrin, and the dissociation constants of these binding sites were determined.
Agatisa-Boyle, Colin Gerard. "NMR ANALYSIS OF INTRACELLULAR AMYLOID-BETA PEPTIDE." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1499265031796677.
Schmidt, Emily Ann. "Spectroscopic investigations of the beta-amyloid peptide." Diss., Columbia, Mo. : University of Missouri-Columbia, 2008. http://hdl.handle.net/10355/5668.
The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on August 14, 2009) Includes bibliographical references.
Bell, Leonard Gerald. "Interactions between #beta#-amyloid peptide and metal ions in amyloid formation." Thesis, University of Sunderland, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337181.
Ma, Xin. "The interaction between amyloid beta peptide and phospholipids." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/29637.
Milton, R. H. "The effects of beta-amyloid peptide on microglial function." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/19221/.
Widenbrant, Martin Johan Olof. "Investigation of amyloid-beta peptide interactions with membrane lipids /." May be available electronically:, 2007. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
Bark, Niklas. "Biophysical studies on aggregation processes and amyloid fibrils with focus on Alzheimer's disease /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-036-2/.
Williamson, Ritchie. "Mechanisms of nerve cell death in Down's syndrome and Alzheimer's disease." Thesis, King's College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271632.
Saurabh, Rahul. "Interaction between the Alzheimer's peptide, beta-amyloid and lipid membrane." Thesis, University of Hull, 2015. http://hydra.hull.ac.uk/resources/hull:13635.
Suen, Ka-chun, and 孫嘉俊. "Molecular signaling of neuronal apoptosis in beta-amyloid peptide neurotoxicity." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B31245961.
Larmuth, Kate Morgan. "Angiotensin-converting enzyme cleavage of the Alzheimer's beta-amyloid peptide." Doctoral thesis, University of Cape Town, 2015. http://hdl.handle.net/11427/16561.
Angiotensin-1 converting enzyme (ACE) is a zinc metallopeptidase that consists of two homologous catalytic domains (N and C) with different substrate specificities. ACE is a central component of the intrinsic brain renin angiotensin-aldosterone system (BRAAS), well renowned as the regulator of blood pressure. The BRAAS has alternate functions that extend beyond fluid and blood pressure homeostasis into areas such as neurological function. As a result, it is implicated in many neurodegenerative diseases including Alzheimer's disease (AD). ACE's specific mechanistic role in AD is not entirely clear and is somewhat controversial. However, it has been shown that ACE hydrolyses the amyloid beta (Aβ) peptide, the putative causative agent of AD. This study aimed to investigate the molecular basis of ACE hydrolysis of Aβ by determining : 1) the kinetic parameters of five different forms of human ACE with various N-terminal amyloid beta (Aβ) substrates; 2) the specific active site determinants of Aβ-domain selectivity; and 3) the high-resolution crystal structures of the N-domain of ACE in complex with Aβ(1-16), Aβ(10-16), Aβ(4-10), the FRET Aβ(4-10)Y and Aβ(35-42) peptides. For the physiological Aβ(1-16) peptide, a novel ACE cleavage site was found at His14/Gln15. Furthermore, Aβ(1-16 ) was preferentially cleaved by the truncated N-domain; however, the presence of an inactive C-domain in full-length ACE greatly reduced enzyme activity and affected domain-selectivity. Two fluorogenic substrates, designed specifically to assess ACE's mechanism of Aβ hydrolysis Aβ(4-10)Q and Aβ(4-10)Y, underwent endoproteolytic cleavage at the Asp7/Ser8 bond. The Aβ(4-10)Q peptide was a poor substrate of ACE but was N-selective, with a selectivity driven largely by interactions with the domain-specific residues of the S2 and S2' pockets. The selectivity of the S2' residues were confirmed with a similar, more physiological, fluorogenic Aβ(4-10)Y peptide. This work provides further understanding towards the substrate determinants of N-selectivity, highlighting the importance of the S2' Ser357. ACE C-domain hydrolysed Aβ(4-10)Y with modest efficiency compared to the other substrates, where hydrolysis under the same conditions did not occur. Moreover, Aβ(4-10)Y also displayed N-domain selectivity. In contrast to Aβ(1-16) and Aβ(410)Q, both sACE and the double C-domain (CC-sACE) construct showed positive domain cooperativity towards Aβ(4-10)Y. The high-resolution crystal structures of the N-domain in complex with five Aβ peptide fragments provided an overlapping, conserved, molecular mechanism of peptide binding and evidence of the enzyme's broad exoprotease activity. In addition to the kinetic and structural studies, ACE's signalling response to the N-selective Aβ(1-16) and Aβ(1-42) was investigated using immunodetection and mass spectrometry. Similar to the ACE inhibitor lisinopril, the Aβ peptides elicited ACE signalling by phosphorylation of the cytoplasmic Ser1270 residue and JNK activation. The signalling response of ACE was coupled to increased ACE activity an d expression on treatment with Aβ(1-42). These studies allowed us to rationalise the increased ACE activity and expression found in AD, may arise through direct interactions with Aβ. This work provides a kinetic, structural and mechanistic understanding of the selective cleavage of Aβ by the N and C catalytic sites of ACE. Due to the broad substrate specificity of the two domains of ACE, and the overarching N- selectivity of Aβ hydrolysis, these findings provide rationale for further in vivo pharmacological studies on the mechanism of action C- domain-selective inhibitors, in the context of AD.
Newby, Francisco Nicolas. "Structural studies of the Alzheimer's amyloid β peptide". Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607712.
Han, Wei. "Development of a coarse-grained protein model and molecular dynamics studies of amyloid-[beta] peptide aggregation /." View abstract or full-text, 2007. http://library.ust.hk/cgi/db/thesis.pl?CHEM%202007%20HAN.
Jimenez, Jeffy Pilar. "Systematic study of amyloid beta peptide conformations implications for alzheimer's disease /." [Tampa, Fla.] : University of South Florida, 2005. http://purl.fcla.edu/fcla/etd/SFE0001286.
Klementieva, Oxana. "Influence of Cu(II) and Glycodendrimers on Amyloid-beta-Peptide Aggregation." Doctoral thesis, Universitat Internacional de Catalunya, 2012. http://hdl.handle.net/10803/78910.
Senile plaques of Alzheimer’s disease patients are composed primarily of the amyloid-β-peptide (Aβ). Recent studies implicate Cu(II) in the aetiology of AD. The role of Cu(II) in ADis currently highly disputed. Influence of Cu(II) on Aβ aggregation and amyloidogenic properties of glycodendrimers were investigated in this thesis. AFM, TEM, SEM, SAXS, FTIR and fluorescence spectroscopy were used to study a morphology and a secondary structure of Aβ-Cu(II) aggregates. The toxic effects of Aβ40-Cu(II) amorphous aggregates was confirmed for neuronal cell lines. It was shown that maltose glycodendrimers can be efficiently used to modulate Alzheimer’s amyloid peptide aggregation and inhibit cell toxicity by facilitating the clustering of amyloid fibrils. These results show that glycodendrimers are promising non-toxic agents in the search for anti-amyloidogenic compounds. It was also suggested that fibril clumping may be anti-amyloid toxicity strategy.
Zhu, Donghui. "Effects of oxidative stress and Alzheimer's amyloid-beta peptide on astrocytes." Diss., Columbia, Mo. : University of Missouri-Columbia, 2006. http://hdl.handle.net/10355/5900.
The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file viewed on (March 3, 2007) Vita. Includes bibliographical references.
Cheung, Yuen-ting, and 張婉婷. "Investigation of neuronal apoptosis and autophagy in beta-amyloid peptide toxicity." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43814840.
Matos, Jason. "In Vitro Characterization of Unmodified and Pyroglutamylated Alzheimer's Amyloid beta peptide." Master's thesis, University of Central Florida, 2014. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/6318.
M.S.
Masters
Molecular Biology and Microbiology
Medicine
Biotechnology; Professional Science Master's Track
Yuen-ting, Cheung. "Investigation of neuronal apoptosis and autophagy in beta-amyloid peptide toxicity." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43814840.
Moustiez, Paul. "Fabrication de nano-aiguilles en silicium en vue d'une détection intracellulaire de biomarqueurs de maladies neurodégénératives." Electronic Thesis or Diss., Université de Lille (2022-....), 2023. https://pepite-depot.univ-lille.fr/ToutIDP/EDENGSYS/2023/2023ULILN054.pdf.
Neurodegenerative diseases are chronic progressive diseases affecting the central nervous system. While these diseases have multifactorial origins, their prevalence increases with age. Due to the progressive aging of the population and the absence of treatment, they are becoming a crucial public health issue. For example, Alzheimer's disease will affect 1 person out of 85 worldwide by 2050. In this context, researchers are studying various options to gain a better understanding of this disease and its pathophysiological mechanisms. They now know that hyperphosphorylation of the Tau protein and the production of toxic forms of beta-amyloid peptides that aggregate into senile plaques are the main causes. The origin of these dysfunctions is still poorly understood but could be elucidated by studying intracellular biochemical mechanisms. In this context, we have conceived an in vitro device based on the use of silicon nanoneedles with the ability to probe the cytoplasm of neuronal cells to detect Alzheimer's biomarkers and monitor their evolution. Our work was based on the development of this sensor, which was divided into 3 points. The first was the fabrication of nanoneedles through the development of cost-effective techniques such as nanosphere lithography followed by wet or dry etching methods. The second point was the optimization of these needles for the bimodal identification of molecules by mass spectrometry (SALDI-MS) and surface-enhanced Raman spectroscopy (SERS). The third point focused on the study of the interaction between our needles and neurons with the aim of capturing biomarkers and preserving cellular integrity. Nanosphere lithography was successfully developed, and the needles were manufactured using two methods: metal assisted chemical etching (MACE) and dry etching by continuous plasma etching. Rhodamine 6G, standard peptides, and beta-amyloid peptides could be detected by SALDI-MS and SERS on our needle arrays. Finally, we observed the biocompatibility of our needles with the cellular environment and characterized their interaction
Kirouac, Lisa. "The Concerted Regulation of Intracellular Signaling by Amyloid Precursor Protein and Aβ Peptide". Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6278.
Shivji, Arif P. "Investigation of #beta#-amyloid (1-40) peptide fibrilization by scanning probe microscopy." Thesis, University of Nottingham, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338493.