Дисертації з теми "Β Peptide"
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Das, Chittaranjan. "Designed β-Hairpin, β-Sheet And Mixed α-β Structures In Synthetic Peptides". Thesis, Indian Institute of Science, 2000. http://hdl.handle.net/2005/263.
Повний текст джерелаChiricotto, Mara. "Hydrodynamic effect on β-amyloid peptide aggregation". Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCC136/document.
Повний текст джерелаThe self-assembly of misfolded amyloid-β (Aβ 1-40/1-42) proteins into insoluble fibrils is strongly linked to the pathogenesis of Alzheimer’s disease (AD). The development of new drugs requires the understanding of the mechanisms leading to fibril formation, and the knowledge of the dynamics and structures of the early metastable oligomers which are the main neurotoxic species. Because atomistic simulations in explicit solvent cannot be performed on very large systems for a significant time scale, we resort to a coarse grained (CG) protein model with an implicit solvent. Our investigation enlightens the role of hydrodynamic interactions (HI) in the kinetics of β-amyloidogenesis, interactions which are essential, when an implicit solvent is used, to model processes occurring in highly crowded like-cell environments, among others.Our approach is based on a multi-scale and multi-physics method that couples Lattice Boltzmann and Molecular Dynamics (LBMD) techniques. In our scheme the solvent- mediated interactions are included naturally. As a first step, we focus on Aβ (16-22) peptide, known to form amyloid fibril alone, and we adopt the high resolution CG OPEP (Optimized Potential for Efficient Protein structure prediction) model, developed in our laboratory. For the first time, we have performed quasi-all-atom simulations for very large systems containing thousands of Aβ (16-22) peptides. After the correct tuning of the key parameters of our coupling in order to obtain the experimental diffusivity of Aβ (16-22) monomer and small oligomers, we have demonstrated that HI speed up the aggregation process of medium (100 peptides) and large (1000 peptides) systems. A detailed characterization of the fluctuating clusters along the trajectories is presented in terms of their sizes and the structural organization of the peptides. Finally, we have investigated how changes in the concentration affect the early aggregation phase of the peptides and their structures
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.
Повний текст джерелаLiu, Yong-Peng. "Total Synthesis of Microsclerodermin D." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASF024.
Повний текст джерелаMicrosclerodermin D is a macrocyclic peptide of marine origin which contains six amino acids, of which two are commercially available: glycine (Gly) and sarcosine (Sar). The four other amino acids: (R)-γ-amino-β-hydroxybutyric acid (GABOB), D-6-chlorotryptophan (6-Cl-Trp), a polyhydroxylated β-amino acid (APTO) and 3-amino-4-hydroxypyrrolidinoacetic acid (PyrrAA) will be accessible by new synthetic routes. Our goal is to develop a modular synthetic route to microsclerodermin D that could be applicable for the preparation of other microsclerodermin family members and analogues thereof. We are also looking forward to make some investigations on their biological activities or potential as anticancer drug
Österlund, Nicklas. "Gas phase studies of the Amyloid-β peptide : Peptide oligomerization and interactions with membrane mimetics". Thesis, Stockholms universitet, Institutionen för biokemi och biofysik, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-155009.
Повний текст джерелаKlementieva, 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.
Повний текст джерелаSenile 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.
Guivernau, Almazán Biuse 1988. "Modulation of Amyloid-β peptide aggregation and neurotoxicity in Alzheimer's disease". Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/585932.
Повний текст джерелаL’agregació del pèptid b-amiloide (Aβ) en forma d’oligòmers i fibres és un esdeveniment central en la patogènesi de la malaltia d’Alzheimer. Aquesta tesi pretén aprofundir en els coneixements actuals sobre la toxicitat causada per l’Aβ així com en l’impacte que tenen els canvis en l’agregació d’aquest, tots dos rellevants per la malaltia d’Alzheimer. Els nostres resultats indiquen que la nitrotirosinació de l’Aβ inhibeix la formació de fibres, afavorint l’estabilització d’oligòmers. Demostrem que els oligòmers d’Aβ nitrat s’uneixen a les dendrites, alterant la funció fisiològica dels receptors d’N-metil- D-aspartat (NMDAR) i provocant disfuncions neuronals i la mort cel·lular. A més, proposem un model d’assemblatge per a les fibres d’Aβ, segons el qual la nitrotirosinació interromp l’elongació de la fibra a causa de la desestabilització dels contactes entre protofibres. Addicionalment, utilitzant un cribratge genòmic en Saccharomyces cerevisiae, hem identificat nous moduladors de la toxicitat causada per Aβ, que podrien ser clau per al desenvolupament de noves estratègies terapèutiques de la malaltia Alzheimer.
Lindberg, Hanna. "Engineering of Affibody molecules targeting the Alzheimer’s-related amyloid β peptide". Doctoral thesis, KTH, Proteinteknologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-173864.
Повний текст джерелаMoore, Claire E. J. "Investigation into glucagon like peptide-1 signalling in pancreatic β-cells". Thesis, University of Leicester, 2008. http://hdl.handle.net/2381/29965.
Повний текст джерелаHöger, Geralin. "Self-Organization of β-Peptide Nucleic Acid Helices for Membrane Scaffolding". Doctoral thesis, Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2019. http://hdl.handle.net/21.11130/00-1735-0000-0003-C187-A.
Повний текст джерелаVILARDO, ELISA. "Il microRNA-101 regola la proteina precursore del peptide β-amiloide". Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2010. http://hdl.handle.net/2108/1175.
Повний текст джерелаIn the pathogenesis of Alzheimer's disease, the expression level of the β-amyloid precursor protein (APP) plays a crucial role. It has been shown that mutations which increase APP protein synthesis, including the duplication of the locus of APP gene in certain families and trisomy of chromosome 21 (containing the APP gene), are sufficient to induce the early form of pathology. Therefore APP gene regulation has been extensively studied and both the promoter and 5’ and 3’ untranslated regions of mRNA have been charachterised. In recent years, the post-transcriptional mechanism of gene expression mediated by microRNAs has been discovered and investigated in several biological mechanisms and cell types. MicroRNAs have been shown to finely modulate the translation of proteins needed for the response to extracellular stimuli, and to define the spatial and temporal expression profiles of genes involved in neuronal development and differentiation. This experimental thesis focused on the question whether microRNAs are significantly involved in APP regulation. Through RNAi , Argonauta-2 gene, a key component of the ribonucleoprotein complex mediating the action of microRNAs, was silenced and APP protein increase was observed. Through bioinformatic analysis, microRNAs potentially interacting with APP have been identified and miR-101, which is enriched in the nervous system, was further investigated. Through expression analysis in rat hippocampus, from 8 days up to 6 months of age, it was observed an inverse correlation between miR-101 levels, which increase, and APP expression, which decreases over time. Using a reporter construct, the ability of miR-101 to inhibit the translation of APP through direct interaction with the messenger 3’UTR was demonstrated. Through inhibition of miR-101 in hippocampal primary cultures, a significant increase of endogenous APP protein was observed, confirming the miRNA regulatory function in the neuronal context. Instead miR-101 over-expression was effective in inducing APP repression at post-transcriptional level. It was also observed that stimulation of hippocampal neurons with IL-1, the first player of neuroinflammation and risk factor for Alzheimers Disease, induces coordinated modulation of APP and miR-101. These data demonstrate the repressive effect of miR-101 on APP under physiological conditions, while the alteration of this regulation is sufficient to induce an increase of APP protein, a condition which is associated to familial Alzheimer’s disease. In view of previous studies, in which miR-101 was shown to be down-regulated in the brains of sporadic cases of Alzheimer's disease, and of data obtained in this work, miR-101 may be a protective regulator of excessive production of β-amyloid precursor protein. The characterization of the signal transduction pathway activated by neuroinflammation, involving miR-101, and the relationship between this pathway and Alzheimer's disease might open a new perspective on the pathogenesis of this neurodegenerative disease.
Pahlke, Denis. "Synthesis, characterisation and sensor-functionalisation of transmembrane β-peptides". Doctoral thesis, Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2018. http://hdl.handle.net/21.11130/00-1735-0000-0003-C180-1.
Повний текст джерелаHu, Zilun. "CONSTRAINED β–PROLINES: I. METHANOPYRROLIDINE β-AMINO ACIDS: SYNTHESIS AND CHARACTERIZATION OF NOVEL C6- SUBSTITUTED ANALOGUES AND PEPTIDE OLIGOMERS II. SYNTHESIS OF 2,2-DISUBSTITUTED PYRROLIDINE-3-CARBOXYLIC ACIDS". Diss., Temple University Libraries, 2015. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/339315.
Повний текст джерелаPh.D.
In the study of structurally restricted cyclic β-amino acids and peptides, methanopyrrolidine-5-carboxylic acids (MetPyr-5-acids), or 5-syn-carboxy-2-azabicyclo[2.1.1] hexanes, and derivatives were investigated. MetPyr-5-acids are a series of highly conformationally constrained β-proline derivatives, which belong to a novel category of β-amino acids utilized as building blocks for the synthesis of β-peptides. These β-peptides lack the backbone hydrogen bonds necessary for folding in the usual manner. Substituents and functional groups in this ring system were envisioned to impact the folding properties and functionalities of the corresponding β-peptides. In the present study, the analogues of MetPyr-5-acids with C6- substitutions were prepared, and the folding properties of their peptides were explored. To introduce different functionalities at C6 in MetPyr-5-acids, 6-syn-hydroxymethyl substituted derivatives were synthesized and were used as key intermediates. In the synthesis of this core structure, the major steps in their preparation included the Michael addition of benzyloxymethyl allyl amine to 3-butynone, followed by UV light irradiation of the diene to afford 5-acetyl-6-benzyloxymethyl-2-azabicyclo[2.1.1]hexane. Haloform (Br2/NaOH) oxidation of the acetyl group leads to the 6-substituted MetPyr-5-acid. Resolution of the racemate was achieved either by resolving (±)-6-syn-benzyloxymethyl-MetPyr-5-acid via a classical crystallization resolution method using (S)-(-)-α-methylbenzylamine, or by chiral preparative HPLC separation of (±)-6-syn-benzyloxymethyl-MetPyr-5-acid methyl ester. The absolute stereochemistry was confirmed by X-ray crystallography of a derivative. Novel analogs with a range of functionalities incorporated at the C6 position in MetPyr-5-acid were synthesized from 6-syn-hydroxymethyl-MetPyr-5-acid methyl ester, and include hydrophilic groups such as hydroxyl, amino, methyl ether, and hydrophobic groups, such as substituted phenyl groups and triazole. From the protected C6-substituted analogs of MetPyr-5-acids, peptide oligomers of C6-benzyloxymethyl-2,4-methanopyrrolidine-b-amino acid were prepared up to the length of octomer in high yields. This series of oligomers were characterized by circular dichroism (CD) and indicated enhanced order of folding uniformity for the tetramer and up, with increasing ordered folding for longer oligomers. The octomer exhibited minimal solvent effects, and was stable with increasing temperature up to 80 °C. Analysis by NMR of the iso-butyric amide capped monomer indicated a mixture of cis/trans conformation favoring the cis conformation. This was slightly different from the C6 unsubstituted iso-butyric amide derivative, which favored the trans conformation. For the dipeptide, the C6-benzyloxymethyl substitution increased the percentage of cis conformation of the dipeptide amide bond, but the major peptide had the trans conformation. This demonstrated that C6 substitutions could shift the cis/trans equilibrium towards the cis conformation. Longer oligomers showed ordered secondary folding structure as demonstrated by the increase in ellipticity per amino acid unit, but was too complicated to be determined by NMR analysis. Both the CD patterns and molecular model calculation predicted that the longer oligomers (tetramer and above) favor the trans conformation. This preference was driven by the backbone dipole effect. II. SYNTHESIS OF 2,2-DISUBSTITUTED PYRROLIDINE-3-CARBOXYLIC ACIDS Due to the perceived steric influence of 2,2-disubstitution in the pyrrolidine-3-carboxylic acid, it is believed that the adjacent amide/peptide bonds should result in a trans amide bond conformation. Because of the difficulty in introducing disubstitution at the hindered C2 position, the synthesis of such derivatives has not been successful. For this reason a new method was introduced to prepare novel derivatives, at the N- and C- termini of protected 2,2-dimethyl pyrrolidine-3-carboxylic acid, i.e., benzyloxycarbonyl protected 2,2-dimethylpyrrolidine-3-carboxylate. This procedure included the Michael addition of 2-nitropropane to dimethyl fumarate, followed by ring closure of the amino ester derived from reduction of the nitro ester providing the pyrrolidinone. Reduction of the pyrrolidinone to the pyrrolidine with borane finished 2,2-dimethylpyrrolidine-3-carboxylate in moderate overall yield. A preliminary set of two amides, iso-butyric amide and 3,5-dichlorobenzamide of this 2,2-dimethylpyrrolidine-3-carboxylate, were also prepared. NMR analysis of this pyrrolidine derivative suggested the amide bonds adopted the trans conformation. It was concluded that steric bulk of the 2,2-disubstitution favorably influenced the trans amide conformation. This demonstrated that trans amide conformation control of a β-proline amide was possible.
Temple University--Theses
Valls, Comamala Victòria 1987. "Targeting aging and Alzheimer's disease : from GM1 ganglioside to amyloide-β peptide". Doctoral thesis, Universitat Pompeu Fabra, 2018. http://hdl.handle.net/10803/664938.
Повний текст джерелаL’envelliment de la població és i serà un gran repte per la nostra societat en els pròxims anys. L’envelliment cerebral està associat amb deficiències cognitives i és el principal factor de risc pel desenvolupament de la malaltia d’Alzheimer. L’Alzheimer és la malaltia neurodegenerativa que més freqüentment provoca demència i és causada per l’agregació del pèptid β-amiloide (Aβ). En aquesta tesis hem demostrat que l’envelliment neuronal condueix a alteracions en el contingut de gangliòsids de les membranes. Particularment, l’increment del gangliòsid GM1 en la membrana condueix a una disminució en l’entrada de calci a través dels receptors de NMDA i a una reducció de les espines dendrítiques. En conjunt, indicant el rol de GM1 en les alteracions en l’aprenentatge i la memòria que es produeixen en l’envelliment. Per una altra banda, hem demostrat l’efecte inhibitori de gamma immunoglobulina humana (IgG) en la inhibició de l’agregació de l’Aβ a través del contacte del fragment d’unió a l’antigen (Fab). Fab s’uneix a Aβ inhibint la progressió de la fibril·lació.
Wahlström, Anna. "NMR studies on interactions between the amyloid β peptide and selected molecules". Doctoral thesis, Stockholms universitet, Institutionen för biokemi och biofysik, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-60346.
Повний текст джерелаAt the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Manuscript. Paper 5: Manuscript.
Chen, Chen. "SINGLE-MOLECULE ANALYSIS OF ALZHEIMER'S β-PEPTIDE OLIGOMER DISASSEMBLY AT PHYSIOLOGICAL CONCENTRATION". UKnowledge, 2014. http://uknowledge.uky.edu/chemistry_etds/31.
Повний текст джерелаMeisch, Jeffrey P. "Human β-defensin 3 peptide is increased and redistributed in Crohn’s ileitis". Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1270735950.
Повний текст джерелаAbelein, Axel. "Modulation of Alzheimer's amyloid β peptide self-assembly : Insights into molecular mechanisms of peptide aggregation associated with Alzheimer's disease". Doctoral thesis, Stockholms universitet, Institutionen för biokemi och biofysik, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-114172.
Повний текст джерелаAt the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.
Selim, Erik. "Solid-phase synthesis of Avian β-Defensin 8". Thesis, Linnéuniversitetet, Institutionen för kemi och biomedicin (KOB), 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-32076.
Повний текст джерелаHuez, Philippe. "Synthèses et analyses conformationnelles de macrocycles aza-β³-peptidiques contenant des atomes d'azote chirogéniques". Thesis, Rennes 1, 2014. http://www.theses.fr/2014REN1S072/document.
Повний текст джерелаThe work depicted here is devoted to the synthesis of pseudopeptides built from aza-β³-aminoacid units, and to their conformational analysis. The results show that the cycles with 8, 16, and 24 bonds each adopt a ground conformation where the relative configuration of the chiral nitrogen atom is fixed in response to specific structural constraints, and despite the nitrogen pyramidal inversion phenomenon. The cycles just undergo equilibrium between two invertomeric forms, and the energetic barrier associated with the macrocycle inversion reveals surprisingly slow considering the size of the compounds. The influence of steric crowding of the side chains on the inversion rate has been carefully studied, but also the transfer of chirality from exocylic elements towards chirotopic nitrogen atoms inside the backbone. A specific chapter is devoted to the 8-membered rings, that reveal the interest of these newly described compounds in the domain of nitrogen chirality
Abelein, Axel. "Modulation of amyloid β peptide self-assembly : Aggregation mechanisms associated with Alzheimer's disease". Licentiate thesis, Stockholms universitet, Institutionen för biokemi och biofysik, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-89078.
Повний текст джерелаTran, Thi Thuy Linh. "Étude théorique de peptides amyloidogènes : Ensemble conformationnel, oligomérisation et inhibition par des ligands peptidomimétiques." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS518.
Повний текст джерелаMany proteins associated with human neurodegenerative diseases are intrinsically disordered. They are proteins which lack stable tertiary or secondary structure under physiological conditions. More specifically, intrinsically disordered proteins (IDPs) undergo various structural conversions between random coil, helical conformations and β-strand structures, these two latter being generally involved in protein-protein recognition. Among about twenty known amyloidogenic peptides related to human degenerative diseases, we focus our study on two disordered proteins: the Amyloid-β peptide (Aβ) associated to the Alzheimer’s disease and the Islet Amyloid Polypeptide (IAPP) involved in type II diabetes. Aβ has two common alloforms of 40 and 42 residues in length, meanwhile IAPP is a 37-residues peptide hormone. Aggregates of Aβ are toxic to the brain cells, meanwhile IAPP fibrillization affects the pancreatic β-cells. The aggregation mechanism of these two peptides is not known in detail, but it was proposed that in solution, these peptides visit various conformations, one of them being rich in β-strands. This would lead to peptide oligomerization, through β-strand / β-strand interactions and eventually to the fibril formation. The aim of our study is to provide insights into the conformational dynamics of these two peptides in monomeric and oligomeric forms. Understanding the early steps of their aggregation is crucial for the development of new effective therapeutic molecules against these amyloid proteins.De nombreuses protéines associées aux maladies neurodégénératives humaines sont intrinsèquement désordonnées. Ce sont des protéines qui sont dépourvues de structure tertiaire ou secondaire stable dans des conditions physiologiques. Plus précisément, les protéines intrinsèquement désordonnées (IDPs) subissent diverses changements conformationnels entre la pelote aléatoire, des conformations hélicoïdales et des structures en feuillet-β, ces deux dernières étant généralement impliquées dans la reconnaissance protéine-protéine. Parmi une vingtaine de peptides amyloïdogènes connus liés aux maladies dégénératives humaines, notre étude porte sur deux protéines désordonnées: le peptide Amyloïde-β (Aβ) associé à la maladie d'Alzheimer et l'Islet Amyloid Polypeptide (IAPP) impliqué dans le diabète de type II. Aβ possède deux alloformes courants de 40 et 42 résidus, tandis que IAPP est une hormone peptidique de 37 résidus. Les agrégats de Aβ sont toxiques pour les cellules du cerveau, tandis que la fibrillisation de IAPP affecte les cellules-β du pancréas. Le mécanisme d'agrégation de ces deux peptides reste encore mal connu, mais il a été proposé qu’en solution, ces peptides visitent différentes conformations, l'une d'entre elles étant riche en feuillets-β. Cela conduirait à l’oligomérisation de ces peptides, par le biais d’interactions feuillet-β / feuillet-β et, éventuellement, à la formation de fibrilles. Le but de notre étude est de mieux caractériser la dynamique conformationnelle de ces deux peptides, dans leur forme monomérique et oligomérique. Comprendre les premières étapes de leur agrégation est crucial pour le développement de nouvelles molécules thérapeutiques efficaces contre ces protéines amyloïdes
Kil, Hyun Joo. "Design & Synthesis of Peptidomimetics Adopting Secondary Structures for Inhibition of p53/MDM2 Protein-protein Interaction and Multiple Myeloma Cell Adhesion." Scholar Commons, 2014. https://scholarcommons.usf.edu/etd/5051.
Повний текст джерелаSadek, Muheeb. "Synthesis and Investigation of Nucleobase Functionalized β-Peptide as SNAREs Model System for Membranefusion". Doctoral thesis, Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2015. http://hdl.handle.net/11858/00-1735-0000-0022-605D-6.
Повний текст джерелаZhu, Maximillian. "Computational studies of the Alzheimer's amyloid-β peptide : from structural ensembles to therapeutic leads". Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608056.
Повний текст джерелаKhamsing, Dany. "Mécanisme d’activation neuronale de mTORC1 et de son altération par le peptide amyloïde β". Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB090.
Повний текст джерелаMTOR is a serine/threonine kinase that belongs to mTORC1 (mTOR complex 1), a key regulator of translation. This complex is involved in LTP (Long Term Potentiation), a form of synaptic plasticity requiring new protein synthesis to reinforce synaptic transmission. The first part of my thesis investigates the mechanism of mTORC1’s regulation in neurons. In non-neuronal cells, mTORC1 pathway is commonly activated by two distinct pathways. On the one hand, amino acids induce mTORC1 recruitment to the membrane of endo-lysosomes where Rheb is enriched and can thus promote mTORC1 activation. On the other hand, growth factors activate mTORC1 via the PI3K/Akt/TSC/Rheb pathway. Our results indicate that neurons are capable of “using” amino acid-induced translocation of mTORC1 to connect synaptic plasticity induction to mTORC1 activation. Indeed, NMDA receptors and BDNF, two main actors of synaptic plasticity, increase mTORC1 recruitment to the membrane of endo-lysosomes even in the absence of amino acids, and activate mTORC1. Using strategies targeting mTORC1 to endo-lysosomes, we show that this mechanism promotes activation of mTORC1 but is not sufficient: Rheb activation is also required. The second part of my project is focused on the regulation of mTORC1 in Alzheimer’s disease, a neurodegenerative pathology characterized by a progressive memory loss. Cognitive deficits are widely believed to result from a progressive dysfunction of synapses, followed by a loss of neurons, both caused by an abnormal accumulation of the amyloid β peptide (Aβ). Data from others show that toxic Aβ oligomers (AβOs) inhibit synaptic plasticity at early stages of the disease. However, the mechanisms remain poorly understood. Several studies indicate an alteration of the mTORC1 pathway. Our results show that AβOs inhibit mTORC1 recruitment to the membrane of endo-lysosomes and that this effect can be rescued by a pharmacological inhibition of AMPK. Thus our data indicate that AβOs inhibit mTORC1 translocation to endo-lysosomal compartments via AMPK. This could lead to the impairment of protein synthesis reported in other studies and thus alter synaptic function
Ratté, Gabriel. "Interaction entre un peptide de β-lactoglobuline bovine (β-lg f1-8) et les protéines du lactosérum : le cas de l’a-lactalbumine". Master's thesis, Université Laval, 2013. http://hdl.handle.net/20.500.11794/24544.
Повний текст джерелаPreliminary observations showed that the self-assembly capacity of a β-lactoglobulin peptide obtained from trypsin hydrolysis (β-lg f1-8) could modify the composition of whey protein mixtures, mainly by reducing the amount of soluble α-lactalbumin (α-la). The goal of this study was to demonstrate the occurrence of interactions between β-lg f1-8 peptide and α-la. A study of the peptide self-assembly process in presence of α-la at 25 and 55 °C showed that the addition of α-la to the original tryptic hydrolysate delays the flocculation of peptide β-lg f1-8 at 55 °C. Adding β-lg f1-8 peptide to α-la modified the solubility profile of the protein at various pH, but its thermal unfolding profile obtained by differential scanning calorimetry (DSC) remained unchanged. All of these observations suggest that the peptide β-lg f1-8 can interact with the α-la via hydrophobic interactions and could be used for developing new strategies for the fractionation of protein mixtures.
Di, Scala Coralie. "Rôle du cholestérol dans l'oligomérisation des peptides β-amyloïdes responsables de la maladie d'Alzheimer". Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM4361.
Повний текст джерелаAlzheimer's disease is the most common neurodegenerative disease whose prevalence increases with age. It is the result of excess β-amyloid peptide (Aß), which self-organizes. This peptide is able to insert into the plasma membrane of cells where their organization in calcium permeable pores triggers the early stages of toxicity. This insertion is directly modulated by the lipid composition of the membrane especially cholesterol. Whereas several studies indicate that cholesterol interacts with and modulates Aß toxicity, the underlying molecular mechanisms remain poorly understood.Using computational, physico-chemical and cellular approaches, we evaluated the role of cholesterol in the insertion of the Aß peptide in the membrane and in the oligomerization process responsible for pore formation. Our study identifies the 22-35 fragment of Aβ as a functional cholesterol-binding domain in which two amino acids are essential: Val24 and Lys28. When incubated with SH-SY5Y cells, the minimal Aβ22-35 peptide caused an increase of Ca2+ entry. This effect was no longer observed in cholesterol-depleted cells and was inhibited by zinc, a classical blocker of amyloid channels. Cholesterol specifically induced a tilted alpha-helical topology of Aβ22-35 which appeared to facilitate the oligomerization process through the establishment of a hydrogen bond network involving Asn27 and Lys28. Finally, our study showed that bexarotene, an anti-Alzheimer compound whose mechanism of action is still under debate, competitively inhibited Aβ insertion into cholesterol-containing membranes and prevented calcium-permeable amyloid pore formation in the plasma membrane of neural cells
Bosson, Anthony. "Impact du peptide amyloïde β sur la signalisation calcique astrocytaire et les interactions neurone-glie". Thesis, Université Grenoble Alpes (ComUE), 2016. http://www.theses.fr/2016GREAV029/document.
Повний текст джерелаAlzheimer’s disease is a neurodegenerative disorder associated with a progressive loss of cognitive functions following synaptic dysfunctions. These synaptic alterations are mainly due to oligomeric forms of amyloid β peptide (Aβo). In humans, these oligomers are already present during the silent phase of the disease and seem to explain synaptic loss and synaptic dysfunctions. However, key mechanisms that initiate synaptic loss and synaptic dysfunctions remain unknown. It is now well established that there is a third component of the synapse, playing major role in morphological and functional synaptic integrity, the astrocyte. Thanks to their processes, astrocytes can enwrap most of synapses and actively participate to morphological and functional changes observed during synaptic activity. Still, their involvement in Alzheimer’s disease is under-investigated.The aim of these thesis works, was to evaluate how Aβo modify astrocytic calcium activity and what could be the repercussions on synaptic activity. We have observed on mice hippocampal acute brain slices a global calcic hyperactivity, within the astrocytic network and inside fine processes. This hyperactivity was dependent on a recently identified astrocytic channel, the TRPA1 channel. This TRPA1-dependent calcic hyperactivity shows up also very early, before amyloid plaques formation, in a transgenic mouse model of Alzheimer’s disease. On the neuronal side, glutamatergic synaptic transmission was increased by Aβo. Interestingly, pharmacological inhibition of TRPA1 could block astrocytic calcium hyperactivity and restore glutamatergic synaptic activity previously disturbed by Aβo. Overall, our data suggests that the astrocyte is a frontline target of Aβo during the prodromal phase of Alzheimer’s disease, and that blockade of astrocytic calcium hyperactivity could preserve synaptic integrity even when Aβo is applied
Fischer, Sabrina [Verfasser], та Armin [Akademischer Betreuer] Geyer. "β-Hairpin-Peptide zur Erkennung von Antikörpern gegen rheumatoide Arthritis / Sabrina Fischer. Betreuer: Armin Geyer". Marburg : Philipps-Universität Marburg, 2015. http://d-nb.info/1068315679/34.
Повний текст джерелаAllan, Laura Elizabeth. "Investigating the effects of the Alzheimer's disease-associated amyloid β-peptide on intracellular calcium homeostasis". Thesis, University of Cambridge, 2010. https://www.repository.cam.ac.uk/handle/1810/283857.
Повний текст джерелаYao, Jun. "Modulateurs et médiateur dans la pathogénie du peptide β- amyloïde dans la maladie d' Alzheimer". Paris 6, 2006. http://www.theses.fr/2006PA066134.
Повний текст джерелаJain, Priyesh. "Design and Synthesis of Beta-Hairpin Peptidomimetics for Modulating Integrin Mediated Cell Adhesion, Abeta Fibrillogenesis and p53-MDM2 Protein-Protein Interactions." Scholar Commons, 2010. http://scholarcommons.usf.edu/etd/3458.
Повний текст джерелаRIZZA, FABIO. "Structural modelling of biological macromolecules: the cases of neurofibromin, bifurcating Electron Transferring Flavoprotein and Amyloid-β (1-16) peptide". Doctoral thesis, Università degli Studi di Milano-Bicocca, 2021. http://hdl.handle.net/10281/310480.
Повний текст джерелаIn this thesis, three independent projects were addressed, sharing the computational approach based on molecular modeling and in particular molecular dynamics. In the first project, the Sec14-PH domain of neurofibromin (NF1) was investigated. The Sec14 domains have been identified in many different proteins, from prokaryotes to humans, serving as exchangers of lipid molecules between membranes, by means of a pocket whose opening is allowed by the motion of a specific alpha-helix (called lid helix). The crystal structure of the NF1-Sec14 domain (of both the wild type and some mutants associated with the onset of neurofibromatosis pathology) has revealed its peculiarity of being structurally coupled to a PH domain that strongly interacts with the lid helix through a long loop (called lid-lock loop). On this basis, a mechanism for the opening of the Sec14 lipid pocket was formulated which would involve a concerted movement of the lid-lock loop, but this movement has actually never been shown. Guided by available experimental data on the thermal denaturation of Sec14-PH domain of NF1, both on the wild type and some neurofibromin-related mutants, several simulations at high temperature were carried out to compare the dynamics of the wild type domain with a pathological mutant associated with the onset of neurofibromatosis. Our simulations lead us to suggest an opening mechanism for the lid helix and provide a hypothesis for the structural and dynamic basis of the onset of the disease in the case of the specific mutant. The second project addressed the study of a protein called EtfAB which catalyzes a recently discovered process known as Flavin-Based Electron Bifurcation (FBEB). This mechanism is only exploited by some anaerobic microorganisms as a third way of energy coupling. So far, four unrelated protein families are known that are able to catalyze FBEB. Among these, EtfAB, catalyzes the electron transfer between the two FAD molecules bound to it. Surprisingly, the distance between these two FADs, as observed in the crystal structure of EtfAB, is 18 Å, whereas biological electron transfer is considered more likely to occur at a maximal distance of 14 Å. To explain this, a possible mechanism has been suggested that could bring the two FAD molecules closer together. Using molecular dynamics, it was possible to test, and discard, the proposed mechanism. Furthermore, with the Density Functional Theory (DFT), it was possible to provide an interpretation to some spectroscopic data regarding the possible electron transfer between the two FAD molecules. In the third project, I collaborated with Prof. Luca Bertini on a project on the production and propagation of some reactive oxygen species (ROS) in the context of the amyloid-beta peptide involved in the pathogenesis of Alzheimer's. In the amyloid hypothesis on the onset of Alzheimer's disease, an important role has been attributed to the damage caused by ROS, produced by a metal ion coordinated to the amyloid peptide itself, in particular by the hydroxyl radical (OH.-). However, the details of how these radicals propagate and react have not yet been clarified. While Prof. Bertini's DFT calculations addressed the oxidative capacities of the hydroxyl radical and the possible reaction products in the context of the amyloid-beta peptide, my molecular dynamics simulations provided an overview on which possible targets of the hydroxyl radical, coordinated to the ion Cu of the complex, could actually react with the hydroxyl radical due to the dynamic motions of the peptide.
Bosch, Morató Mònica 1986. "The Role of intracellular amyloid β-peptide in the pathophysiology of GNE myopathy and Alzheimer's disease". Doctoral thesis, Universitat Pompeu Fabra, 2015. http://hdl.handle.net/10803/650351.
Повний текст джерелаEl pèptid β-amiloide (Aβ) s’acumula en diverses malalties com la miopatia de GNE i la Malaltia d’Alzheimer (MA). La miopatia de GNE és una malaltia del múscul esquelètic causada per mutacions al gen UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), que codifica un enzim clau en la biosíntesis de l’àcid siàlic. El GNE mutat produeixen un enzim hipofuncional i una conseqüent disminució de l’àcid siàlic cel·lular. Hem vist que la hiposialització afavoreix l’endocitosi de l’Aβ en cèl·lules musculars, la qual és dependent de clatrina i de l’heparà sulfat proteoglicà. A més, hem observat que l’Aβ intracel·lular indueix l’apoptosi en cèl·lules musculars mitjançant la inhibició de l’Akt. Així, la fosforilació de l’Akt es troba reduïda i l’apoptosi induïda en mioblasts d’un pacient amb la miopatia de GNE. Finalment, a través d’un cribratge del genoma complert de Saccharomyces cerevisiae, hem identificat nous moduladors de la toxicitat per Aβ que inclouen components de la cadena respiratòria mitocondrial i membres de la via de senyalització del Ca2+. En resum, aquest estudi ofereix una millor comprensió del rol de l’Aβ en la miopatia de GNE i la MA.
Wan, Yang. "Synthesis of β,γ-diamino acids and their use to design new analogues of the antimicrobial peptide Gramicidin Septide antimicrobien, la Gramicidine S". Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS407/document.
Повний текст джерелаIn our group, we are interested in developing peptides containing β,γ-diamino acids . Along with many other peptides containing unnatural amino acids, they have shown the ability to possess stable conformations and/or interesting biological activities. Moreover, those peptides are usually more resistant to proteolysis. In order to synthesize stereopure γ-amino acids, we have developed a synthetic route using Blaise reaction and subsequent diastereoselective reduction as key reactions. Through applying this method, we have synthesized β,γ-diamino acids derived from D-phenylalanine and L-glutamic acid. The former β,γ-diamino acid was used for designing antimicrobial peptide gramicidin S analogues. Compared with mother molecule, the analogues exerted much less host cell cytotoxicity while remaining interesting antibacterial activity. Meanwhile, it gave us more knowledge for further developing analogues of gramicidin S as well as other antimicrobial peptides. We also paid lots of effort to efficiently synthesize cyclic β,γ-diamino acids starting from L-glutamic acid. Interestingly, when oligomers incorporating this β,γ-diamino acids and α-amino acids, they have shown the potential to adopt stable conformations. The following studies will be continuously investigated
Bettale, Jennifer Dawn. "Progress Toward Theonellamide F." BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/3022.
Повний текст джерелаLesma, Jacopo. "β-Hairpin peptidomimetics as inhibitors of hIAPP amyloid protein aggregation : design, synthesis and evaluation Introducing sequential aza-amino acids units induces repeated ß-turns and helical conformations in peptides β-Hairpin peptide mimics decrease human Islet Amyloid Polypeptide (hIAPP) Aggregation". Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASQ018.
Повний текст джерелаType 2 Diabetes (T2D) with over 400 million cases worldwide represents 90% of total diabetes cases. T2D is a degenerative disease associated with insulin resistance and pancreatic β-cells death linked to deposits of the amyloid protein hIAPP (also called amylin), that are observed in the pancreas of over 95% of the T2D patients. The treatments currently available are symptomatic and characterized either by significant side effects or low impact on the incidence of related pathologies and mortality reduction. Thus, to find an etiological treatment for T2D, targeting hIAPP has become a promising strategy to explore. To date, few classes of compounds have been proposed to inhibit hIAPP aggregation process. However, to the best of our knowledge, only very scarce examples of acyclic β-hairpin have been described. Since hIAPP aggregation is a highly complex and dynamic process, we hypothesized that flexible β-hairpins could better adapt to different hIAPP conformations formed during the aggregation process. Our design was based on flexible piperidine pyrrolidine β-turn inducers linked to two different arms inspired by the primary sequence of hIAPP peptide, with a peptidic self-recognition element (SRE) derived from the hIAPP amyloidogenic sequence facing to a peptidic or peptidomimetic blocking sequence. In order to confirm β-hairpin conformation of our inhibitors, our compounds were conformationally studied by NMR and in few cases by molecular dynamics. Then, their ability to interfere with hIAPP aggregation process was primarily evaluated by thioflavin-T fluorescence spectroscopy. The most promising compounds of the series were then investigated by other biophysical assays such as transmission electron microscopy (TEM), capillary electrophoresis (CE) and IMS-MS. The best compounds of the series were then studied to determine their ability to reduce hIAPP toxicity on rat INS-1 pancreatic cells.Having proved the possibility to modulate hIAPP aggregation process employing small acyclic β-hairpin mimics bearing both peptidic and peptidomimetic arms, we then focused our attention on the development of fluorinated hairpin peptidomimetics that, until now, have never been explored either as hIAPP aggregation inhibitors, nor, to our knowledge, more broadly in medicinal chemistry. The preparation of these fluorinated analogues had the double scope to investigate how fluorine, with its unique characteristics, could influence both the activity and the conformations of our inhibitors. In conclusion, the work presented in this thesis provides valuable insight for the development of new acyclic β-hairpin mimics as modulators of hIAPP and potentially new fluorinated tools to further investigate its aggregation process
Nicklagård, Erik. "Quantification of Alzheimer DiseaseAmyloid β Peptide 43 in Human BrainWith a Newly Developed Enzyme-LinkedImmunosorbent Assay (ELISA)". Thesis, Linköpings universitet, Biokemi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-70490.
Повний текст джерелаSantini, Sébastien. "Flexibilité et changements topologiques de la protéine prion et du peptide β-amyloi͏̈de d'Alzheimer par simulations numériques". Aix-Marseille 1, 2004. http://www.theses.fr/2004AIX11029.
Повний текст джерелаLaporte, Vincent. "Elimination du peptide β-amyloi͏̈de par les cellules microgliales dans la maladie d'Alzheimer : implication du récepteur LRP". Université Louis Pasteur (Strasbourg) (1971-2008), 2002. http://www.theses.fr/2002STR13087.
Повний текст джерелаThe senile plaque is one of the fundamental markers of Alzheimer's disease. It is an extracellular lesion made up mainly of a deposit of ?eta-amyloid [A?] peptide fibrils. Accumulation of A? fibrils would induce activation of microglial cells which would result in a chronic release of inflammatory proteins. This immunological process could be the cause of the cerebral atrophy observed in patients' brain. It is thus necessary to limit the formation of the amyloid deposits by inhibiting the synthesis of A? peptide or improve its degradation. Microglia which border the amyloid deposit present functions of phagocytosis. Thus, they could be able to ingest amyloid fibres and to control the appearance of the pathological amyloid deposits in elderly. Such observations were carried out in vitro. However, studies relating interactions between microglia and A? peptide use systems in which the modeling of amyloid deposit is not perfect. This is why we developed a new model of study in which (a) murine microglial cell line established at the laboratory and (b) a new model of amyloid deposit are used. In this work, we characterized the different cell types present in the culture of microglia and we presented the model of amyloid deposit, in which A? peptide fibrils are immobilized onto heat-killed yeast surface. Lastly, we studied the fate of these artificial amyloid deposits when they are placed in contact with microglial cells: they are ingested by phagocytosis. The identification of the microglial cell receptors implied in this process was also started
Erdélyi, Máté. "Towards the Development of Photoswitchable β-Hairpin Mimetics". Doctoral thesis, Uppsala universitet, Avdelningen för organisk kemi, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4057.
Повний текст джерелаFujita, Naotaka. "Noninvasive longitudinal quantification of β-cell mass with [111In]-labeled exendin-4". Doctoral thesis, Kyoto University, 2020. http://hdl.handle.net/2433/245834.
Повний текст джерела0048
新制・課程博士
博士(医学)
甲第22149号
医博第4540号
新制||医||1039(附属図書館)
京都大学大学院医学研究科医学専攻
(主査)教授 川口 義弥, 教授 上本 伸二, 教授 富樫 かおり
学位規則第4条第1項該当
Doctor of Medical Science
Kyoto University
DFAM
Megy, Simon. "Etude de la structure de la protéine β [Bêta]-Caténine et de son interaction avec la protéine β [Bêta]-TrCP par RMN et modélisation moléculaire". Paris 6, 2005. http://www.theses.fr/2005PA066331.
Повний текст джерелаGanga, Ramu Vasanthakumar [Verfasser]. "Studies on Chemical Synthesis of Peptides: Efficient Synthetic Methods for β-Amino Acids, Azides, Amino Acid Hydroxamates and Esters : Methodologies in peptide synthesis / Vasanthakumar Ganga Ramu". München : GRIN Verlag, 2011. http://d-nb.info/119000478X/34.
Повний текст джерелаDietrich, Laura [Verfasser], Susanne [Akademischer Betreuer] Brakmann та Tom N. [Gutachter] Grossmann. "Zellgängige Peptide zur Inhibition des Wnt/β-Catenin Signalweges / Laura Dietrich ; Gutachter: Tom N. Grossmann ; Betreuer: Susanne Brakmann". Dortmund : Universitätsbibliothek Dortmund, 2017. http://d-nb.info/1137702125/34.
Повний текст джерелаMOORE, COURTNEY MARIE. "EFFECT OF A HETEROBIVALENT GLUCAGON LIKE PEPTIDE-1 LINKED TO CHOLECYSTOKININ ON INSULIN SECRETION IN PANCREATIC β-CELLS". Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/613295.
Повний текст джерелаMari, Meropi. "Investigating the aggregation of β-amyloid peptide (Aβ₄₂) and its interactions with lipid bilayers using advanced microscopy techniques". Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/8889.
Повний текст джерелаLeeb, Elena [Verfasser]. "Ways for a targeted enzymatic hydrolysis of β-lactoglobulin - Control of reaction kinetics and peptide fractionation / Elena Leeb". München : Verlag Dr. Hut, 2021. http://d-nb.info/1235279324/34.
Повний текст джерелаMahalakshmi, R. "Aromatic Interactions In Peptides : Designed Helices And β-Hairpins". Thesis, 2006. http://hdl.handle.net/2005/458.
Повний текст джерела