Relevant bibliographies by topics / APP and amyloid fragments / Dissertations / Theses

Dissertations / Theses on the topic 'APP and amyloid fragments'

To see the other types of publications on this topic, follow the link: APP and amyloid fragments.
Author: Grafiati
Published: 8 June 2024

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles

Select a source type:

Consult the top 50 dissertations / theses for your research on the topic 'APP and amyloid fragments.'

Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.

You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.

Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.

1

Vigier, Maxime. "Influence des lipides membranaires sur les interactions protéiques liées aux anomalies endolysosomales dans un modèle neuronal de la maladie d'Alzheimer." Electronic Thesis or Diss., Université de Lorraine, 2022. http://www.theses.fr/2022LORR0331.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
La maladie d'Alzheimer (MA) est une pathologie complexe et multifactorielle pour laquelle il n'existe actuellement aucun traitement. Plusieurs hypothèses ont été proposées pour expliquer l'apparition et la progression de cette maladie, dont la cascade amyloïde, qui prédomine dans le domaine de la recherche depuis 30 ans. La voie amyloïdogène nécessite l'endocytose de la protéine APP dans les endosomes précoces où elle subit deux clivages protéolytiques, d'abord par la β-sécrétase pour produire le fragment C99, puis par la γ-sécrétase pour produire le peptide Aβ. L'une des hypothèses actuelles est que les anomalies de l'endocytose et le dysfonctionnement du système endolysosomal dans les neurones constitueraient un des mécanismes neuropathologiques précoces de la MA, bien avant la cascade neurotoxique générée par Aβ et les dépôts amyloïdes. Nous défendons l'hypothèse que des modifications de l'organisation membranaire, notamment au cours du vieillissement ou dues à des déséquilibres lipidiques, pourraient exacerber ou favoriser ces dysfonctionnements. Pour cette étude, nous avons utilisé un modèle de neuroblastome humain surexprimant la protéine mutante APPswe. Nous avons tout d'abord vérifié la présence d'anomalies endolysosomales typiques de la MA (endosomes hypertrophiés, trafic vésiculaire bloqué), auxquelles nous avons également associé une faible production d'exosomes, conditions de stress chronique que nous avons corrélées à la mort neuronale. Incriminant dans un premier temps une production continue d'Aβ dans ces cellules, nous avons cherché à réduire son impact en inhibant l'activité γ-sécrétase. Cela n'a pas amélioré le stress, mais l'a au contraire aggravé, ce qui nous a conduit à considérer que c'est le fragment C99 de l'APP, c'est-à-dire le substrat de la production d'Aβ, qui est le produit amyloïde central de la cascade neurotoxique observée dans les cellules surexprimant l'APP. Les effets délétères du C99 doivent se produire avant ceux de l'Aβ, expliquant la précocité connue des altérations endolysosomales. S'accumulant à la suite de l'inhibition de la γ-sécrétase, le fragment C99 interagit davantage avec la protéine Rab5, spécifique de l'endosome précoce. La maturation de cette dernière est ainsi empêchée, bloquant le trafic vésiculaire du système endolysosomal. Comme les interactions entre C99 et Rab5 se produisent au niveau de la membrane des endosomes, nous avons modifié la composition lipidique de la bicouche et exploré les conséquences sur ces interactions. À cette fin, nous avons traité des cellules SH-SY5Y-APPswe par de l'acide docosahexaénoïque (DHA, C22:6 n-3), le principal acide gras polyinsaturé des membranes neuronales et connu pour ses propriétés neuroprotectrices contre le stress amyloïde et la MA. L'effet bénéfique attendu sur la survie neuronale a bien été observé, en parallèle au déblocage du trafic endolysosomal et à la production d'exosomes. Tous ces changements ont été corrélés à une dispersion entre C99 et Rab5 dans la membrane, suggérant que le traitement par le DHA a pu initier un remodelage membranaire. Ce remodelage peut conduire à une relocalisation des protéines, les endosomes pouvant alors échanger Rab5 contre Rab7 et évoluer en endosomes tardifs, levant ainsi le blocage initial. À notre connaissance, il s'agit de la première preuve que le DHA peut corriger un phénotype directement lié à la MA, mais sa capacité à remodeler la membrane neuronale a déjà été démontrée par notre équipe pour préserver la signalisation par le facteur neurotrophique CNTF dans le cerveau de souris âgées. Nous ignorons quels principes mécanistiques pourraient régir ces effets bénéfiques, certainement non spécifiques, mais nous supposons qu'en préservant l'organisation des membranes des neurones âgés ou soumis à un stress chronique, ils pourraient prévenir ou restaurer une partie des dommages subis, augmenter les chances de survie des neurones et ainsi ralentir le développement de la MA
Alzheimer's disease (AD) is a complex and multifactorial pathology for which there is no current treatment. Several hypotheses have been proposed to explain the onset and progression of this disease, including the amyloid cascade, which predominates the field of research for the past 30 years. The amyloidogenic pathway requires the endocytosis of the APP protein in early endosomes where it undergoes two proteolytic cleavages, first by β-secretase to produce the C99 fragment, and then by γ-secretase to produce the Aβ peptide. One of the current hypotheses is that abnormalities of endocytosis and dysfunction of the endolysosomal system in neurons would constitute one of the early neuropathological mechanisms of AD, well before the neurotoxic cascade generated by Aβ and amyloid deposits. We advocate the hypothesis that changes in membrane organization, particularly during aging or due to lipid imbalances, may exacerbate or promote these dysfunctions. For this study, we used a human neuroblastoma model overexpressing the mutant protein APPswe. We first verified the presence of typical AD endolysosomal abnormalities (enlarged endosomes, blocked vesicular trafficking), to which we also associated low exosome production, chronic stress conditions that we correlated with neuronal death. Initially incriminating continuously produced Aβ in these cells, we sought to reduce its impact by inhibiting γ-secretase activity. This did not ameliorate the stress, but instead aggravated it, leading us to consider that it is the C99 fragment of APP, i.e. the substrate of Aβ production, that is the central amyloid product in the neurotoxic cascade seen in APP-overexpressing cells. The deleterious effects of C99 must occur before those of Aβ, explaining the known precocity of endolysosomal alterations. Accumulating as a result of γ-secretase inhibition, the C99 fragment interacts further with the early endosome-specific Rab5 protein. Maturation of the latter is thus prevented, blocking vesicular trafficking of the endolysosomal system. As the interactions between C99 and Rab5 occur at the membrane level of endosomes, we have modified the lipid composition of the bilayer and explored the consequences on these interactions. For this purpose, we treated SH-SY5Y-APPswe cells with docosahexaenoic acid (DHA, C22:6 n-3), the major polyunsaturated fatty acid in neuronal membranes and known for its neuroprotective properties against Aβ toxicity and AD. The expected beneficial effect on neuronal survival was indeed observed, in parallel with the unblocking of endolysosomal trafficking and exosomal production. All these changes were correlated with a dispersion between C99 and Rab5 in the membrane, suggesting that DHA treatment may initiate membrane remodeling. This remodeling may lead to protein relocalization, whereby endosomes may exchange Rab5 for Rab7 to evolve into late endosomes, thereby overcoming the initial blockage. To our knowledge, this is the first evidence that DHA can correct a phenotype directly related to AD, but its ability to remodel the neuronal membrane was previously demonstrated by our team to preserve the neurotrophic CNTF signaling in the brain of aged mice. We do not know what mechanistic principles might govern these beneficial effects, which are certainly non-specific, but we assume that by preserving the organization of the membranes of aged or chronically stressed neurons, they may prevent or restore some of the damage suffered, increase the chances of neuronal survival and thus slow AD development
2

Vingtdeux-Didier, Valérie. "Aspects moléculaires et cellulaires impliqués dans le clivage ou la dégradation des fragments carboxy-terminaux et du domaine intracellulaire du Précurseur du Peptide Amyloïde (APP-CTFs et AICD)." Lille 2, 2006. http://www.theses.fr/2006LIL2S036.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
La maladie d'Alzheimer (MA) se caractérise par la présence de deux lésions : les dégénérescences neurofibrillaires (DNF) et les dépôts amyloïdes, ces derniers résultants de l'accumulation du peptide bêta-amyloïde. Ce peptide dérive du catabolisme de l'APP (Précurseur du Peptide Amyloïde). Les travaux réalisés au laboratoire montrent qu'il existe une relation entre le métabolisme de l'APP et la progression des DNF qui s'illustre par une perte du domaine intracellulaire et des fragments carboxy-terminaux de l'APP (AICD et APP-CTFs). La phosphorylation de ces derniers est également modifiée dans la MA. Notre objectif a donc été de déterminer quels étaient les facteurs susceptibles de diminuer les APP-CTFs et l'AICD. Nos travaux ont permis de montrer que la phosphorylation des APP-CTFs pouvait réguler leur clivage via l'activité γ-sécrétase, que la voie endosome/lysosome est impliquée dans la dégradation de l'AICD et ils décrivent une nouvelle voie de sécrétion pour l'APP et ses dérivés
Alzheimer's disease (AD) is characterized by two distinct pathologies: neurofibrillary tangles (NFT) and extracellular amyloid plaques composed of beta-amyloid peptide (Abeta). Abeta derive from the catabolism of the Amyloid Precursor Protein (APP). A relationship between APP metabolism and NFT is observed in AD. This relation is illustrated by a significant decrease of APP-CTFs and AIDD, which correlated with the progression of NFT. APP-CTFs phosphorylation is also modified in AD. The main objectives of this thesis were to identify the degradations pathways of APP-CTFs and AICD. Our results demonstrated that increase in the phosphorylation of APP-CTFs facilitates their processing by the gamma-secretase. Moreover, our data demonstrate for the first time that the endosome/lysosome pathway mediates the degradation of AICD and we describe a novel secretion pathway of APP catabolic derivatives
3

Lundmark, Katarzyna. "Studies on pathogenesis of experimental AA amyloidosis : effects of amyloid enhancing factor and amyloid-like fibrils in rapid amyloid induction /." Linköping : Univ, 2001. http://www.bibl.liu.se/liupubl/disp/disp2001/med711s.pdf.

Full text
APA, Harvard, Vancouver, ISO, and other styles
4

Paz, Sandra Isabel Moreira Pinto Vieira Guerra e. "Phosphorylation-dependent Alzheimer's Amyloid precursor protein (APP) targeting." Doctoral thesis, Universidade de Aveiro, 2006. http://hdl.handle.net/10773/4629.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
Doutoramento em Biologia
A Doença de Alzheimer (DA) é uma das doenças neurodegenerativas mais comuns, e apresenta uma incidência mundial de 2-7% em indivíduos com mais de 65 anos e de cerca de 15% em indivíduos acima dos 85 anos de idade. Apesar da sua etiologia multifactorial, há uma correlação bem descrita entre esta patologia e um peptídeo neurotóxico denominado Abeta. Este peptídeo deriva fisiológica e proteoliticamente de uma glicoproteína transmembranar com características de receptor: a Proteína Percursora de Amilóide de Alzheimer (PPA). As possíveis funções fisiológicas da proteína PPA, o seu destino e vias de processamento celulares, conjuntamente com possíveis proteínas celulares que com ela interajam, são assim tópicos de interesse e objectos de investigação científica mundial. Neste contexto tem sido amplamente descrito o envolvimento do processo de fosforilação de proteínas, uma importante modificação pós-transducional que regula muitos e variados acontecimentos intracelulares, na regulação do processamento da PPA. Apesar do exposto, muito pouco é conhecido acerca da fosforilação directa da própria PPA. Esta proteína possui na sua estrutura primária sequências consenso para fosforilação, quer no seu ectodomínio quer no seu domínio intracelular, já descritas como sofrendo fosforilação “in vitro” e “in vivo”. O resíduo Serina 655 pertence a um motivo funcional da APP, 653YTSI656, que forma um sinal de internalização e/ou de “sorting” basolateral. Este domínio é também o local de ligação para a APPBP2, uma proteína que interage com os microtubulos da célula. Embora ainda mal elucidados, os mecanismos pelos quais a fosforilação proteica regula o processamento da PPA parecem incluir uma alteração no tráfego desta proteína, sugerindo que o domínio fosforilável 653YTSI656 desempenha um papel importante nesse processo. Esta dissertação visou assim contribuir para elucidar o papel da fosforilação directa da molécula de APP, mais especificamente no seu resíduo Serina 655, na regulação do direcionamento e tráfego subcelular da proteína, e nas suas possíveis clivagens proteolíticas. De forma a respondermos a essas questões desenvolvemos um modelo experimental para seguir o tráfego intracelular, que usa uma combinação de biologia molecular, técnicas de microscopia de epifluorescência e técnicas de cultura celular. Os resultados obtidos implicam este resíduo como um sinal de direcionamento subcelular da proteína APP, e revelam como o redireccionamento desta proteína por fosforilação favorece um tipo de processamento não amiloidogénico desta. Adicionalmente, a fosforilação do resíduo Serina 655 parece possuir um papel regulador da actividade da PPA como molécula de transdução de sinais. As implicações destas observações na DA e em novas aplicações terapêuticas para a doença são subsequentemente discutidas.
Alzheimer’s Disease (AD) is a common neurodegenerative disease affecting individuals worldwide with an incidence of 2-7% of post-65 and 15% of post-85 years old. This disease is multifactorial in its etiology but central to its pathology is a neurotoxic peptide termed Abeta. This peptide is physiologically derived by a proteolytic process on the transmembranar Alzheimer’s Amyloid Precursor Protein (APP). Protein phosphorylation-dependent APP processing has been widely described and although the mechanisms involved remain far from clarified, alterations in APP trafficking seem to occur as part of the answer. Furthermore, the occurrence of consensus phosphorylation sites in the APP intracellular domain has been known for long, but little was known regarding the direct phosphorylation of APP. Efforts in unravelling the role of these domains are finally being successful in placing them as key control points in APP targeting and processing. Among these consensus sequences, the less studied 653YTSI656 motif forms a characteristic internalisation and/or basolateral sorting signal sequence, and is known to be the binding site for a microtubuleinteracting protein (APPBP2). Phosphorylation of this motif was thus suggested to be involved in APP targeting regulation, hitherto all attempts failed to confirm it or even to reveal substantial evidences. In this project, the role of the 653YTSI656 idomain, and in particular the phosphorylatable serine 655, in APP trafficking and proteolytic processing was studied. In order to address this question a new experimental methodology was developed, which coupled molecular biology, fluorescence imaging, and cell culture techniques. APP point mutants, mimicking serine 655 phosphorylatedand dephosphorylated-status, and tagged with the green-fluorescent protein, were used to study protein trafficking dynamics and processing. Results obtained place serine 655 phosphorylation as a key signal in APP sorting and targeting to specific subcellular locations. Also of high relevance was the observed implication of serine 655 phosphorylation as a regulatory mechanism that maybe involved in controlling APP function as a signal transducer. The implications of these observations in AD pathogenesis and therapeutic approaches are discussed.
FCT - PRAXIS XXI/BD/16218/98
FCT - POCTI/BCI/34349/1999
Project DIADEM, QLK3-CT- 2001/02362
Fundação Calouste Gulbenkian
Fundação Astrazeneca
5

Rocha, Joana Fernandes da. "Characterizing Alzeimer's amyloid precursor protein (APP) neurotrophic functions." Doctoral thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22225.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
Doutoramento em Biomedicina
The Amyloid Precursor Protein (APP) is a type 1 membrane glycoprotein, mainly known as the precursor of the amyloid β-peptide, a central player in Alzheimer’s disease. Nevertheless, APP has been established as a neuromodulator of developing and mature nervous system. Alterations in the level or activity of APP and APP fragments seem to play a critical role in several neurodegenerative and neurodevelopment disorders. APP is a complex molecule due to the intricate relationships between its intracellular trafficking, posttranslational modifications, proteolytic cleavages, and multiple protein interactors. Various studies currently address the physiological roles of APP and its fragments, but there are contradictory results and missing pieces that need further work. The main objective of this thesis was to contribute to the characterization of the role of APP in neuronal differentiation. Particularly, we focused on mechanisms mediated by APP, its fragment sAPP, and APP phosphorylation at serine 655. First, we characterized the APP protein in Retinoic Acid (RA)-induced SHSY5Y cell differentiation. The comprehensive analysis of this model exposed a biphasic temporal response: a first early phase (D0-D4), where a sAPP/APP peak assists the emergence of new processes and their elongation into neurites; and a second phase (D4-D8) when increased holoAPP protein levels are necessary to sustain neuritic elongation and stabilization. In line with our main aim, we subsequently characterized the relationship between APP and the neurotrophic EGF-EGFR-ERK signaling pathway. We showed, for the first time, that APP interacts with proEGF, and confirmed the interaction with EGFR. Furthermore, we showed that combined APP and EGF have a synergistic effect on neuronal-like differentiation, related to enhanced ERK1/2 activation, and observed that APP modulates EGFR expression levels and trafficking. Both ERK1/2 activation and EGFR seem to be modulated by the APP S655 phosphorylation state, and phosphorylation at this residue favours dendritogenesis in mice cortical neurons. Finally, we focused on discovering APP protein interactors dependent on S655 phosphorylation and with a role in neuronal differentiation. SH-SY5Y differentiated cells, overexpressing APPWt or S655 phosphomutants, were used to immunoprecipitate the specific APP proteins and their respective interacting partners, later identified by mass spectrometry. The dephosphoS655 APP interactome was enriched in functions associated with cytoskeleton organization, and these cells were particularly associated with actin remodeling. The phosphoS655 APP interactome included proteins involved in the regulation of survival and differentiation, and in various signaling pathways, correlating well with an enhanced neurite outgrowth displayed by these cells. We hope that the knowledge here gathered can contribute to a better comprehension of APP-driven neurotrophic roles and underlying mechanisms.
A Proteína Precursora de Amilóide (APP) é uma proteína membranar mais conhecida por ser precursora do péptido Amilóide β, tendo por isso um papel central na doença de Alzheimer. Não obstante, a APP tem sido reconhecida como neuromodulador do sistema nervoso central. Alterações nos níveis ou na atividade da APP e seus fragmentos estão implicadas em diferentes doenças neurológicas. As relações entre o seu transporte intracelular, modificações pós-traducionais, corte proteolítico, e proteínas com as quais interage são complexas e multifacetadas. Talvez por isso, estudos focados no papel fisiológico da APP apresentem resultados contraditórios e muitas questões em aberto. O objetivo deste trabalho consistiu na caracterização do papel fisiológico da APP na diferenciação neuronal. Particularmente, focámo-nos nos mecanismos mediados pela APP e fragmento sAPP, e a fosforilação da APP no resíduo serina 655. Inicialmente, caracterizámos a proteína APP ao longo da diferenciação de células SH-SY5Y com ácido retinóico (RA). A análise sistemática deste modelo permitiu delimitar uma resposta bifásica: na primeira fase (D0-D4), um pico de sAPP/APP acompanha o aparecimento de novos processos e o crescimento a neurites; na segunda fase (D4-D8) o aumento nos níveis da APP suporta o crescimento e manutenção das neurites. Caracterizámos posteriormente a relação entre a APP e a via de sinalização EGF-EGFR-ERK na diferenciação neuronal. Demonstrámos, pela primeira vez, que a APP interage com o proEGF, e confirmámos a sua ligação ao EGFR. Adicionalmente, observámos que a APP e o EGF têm um efeito sinérgico na diferenciação tipo-neuronal e aumento da ativação da ERK1/2, e que a APP afeta os níveis e transporte do EGFR. Estes mecanismos são modulados pela fosforilação da APP na S655, que favorece a dendritogénese em neurónios corticais de ratinho. Por último, focámo-nos na identificação de proteínas interatoras da APP dependentes da fosforilação em S655 e com função na diferenciação neuronal. Usando células SH-SY5Y diferenciadas e a sobrexpressar a APPWt ou fosfomutantes da S655, imunoprecipitámos as diferentes APPs e seus interatores, posteriormente identificados por espectrometria de massa. O interatoma da APP desfosforilada é enriquecido em funções associadas à organização do citoesqueleto, levando a uma maior reorganização da actina. O interatoma da APP fosforilada incluí proteínas envolvidas na regulação de sobrevivência e diferenciação, e em várias vias de sinalização, o que se correlaciona com o favorecimento de neurites nestas células. Com este trabalho esperamos ter contribuído para uma melhor compreensão do papel neurotrófico da APP e dos mecanismos subjacentes a este.
6

Kim, Joung-Hun. "Electrophysiological and biochemical studies of #beta#-amyloid precursor protein fragments." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394383.

Full text
APA, Harvard, Vancouver, ISO, and other styles
7

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/.

Full text
APA, Harvard, Vancouver, ISO, and other styles
8

Crawford, Fiona Caroline. "Chromosome 21, the amyloid precursor gene and Alzheimer's disease." Thesis, University of London, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360759.

Full text
APA, Harvard, Vancouver, ISO, and other styles
9

Bowes, Simone. "Processing of Alzheimer's amyloid precursor protein in cultured cells." Thesis, Sheffield Hallam University, 1999. http://shura.shu.ac.uk/19377/.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
The deposition in the brain of the 4 kDa beta-amyloid peptide (betaA4), from amyloid precursor protein (APP), is a key pathology in Alzheimer's disease (AD). The single APP gene is spliced to give 3 major isoforms. In the majority of body tissues, the most common APP isoforms are APP[751] and APP[770], which both contain a Kunitz protease inhibitor (KPI) domain, APP[695] is predominant in the brain. APP is processed through several pathways, not all of which lead to betaA4 production. Central nervous system (CNS) neurones in vivo secrete betaA4, which can be detected in the cerebrospinal fluid, though it is unknown why betaA4 is deposited in the brain in AD. NTera2 (NT2) cells derived from a human teratocarcinoma were used as a model of APP processing. Retinoic acid induces these cells to differentiate into a neuronal phenotype (NT2N cells), which has been shown to closely resemble immature human CNS neurones. Both cell types produce high levels of endogenous APP.Intracellular and secreted APP was studied in both cell types by means of western blotting and immunoprecipitation with a panel of antibodies. It was found that NT2 cells predominantly make and secrete KPI containing APP. NT2N cells make and secrete predominantly APP[695] though some KPI containing APP is also present. There is evidence that neurones in the AD brain are in a state of stress, which could increase levels of APP due to a heat shock promotor region in its gene. To investigate this, NT2 cells were subjected to a heat shock, which resulted in increased levels of heat shock protein (HSP) and APP. KPI containing APP predominated, but there was no corresponding increase in secreted APP. Both cell types were also serum deprived, which resulted in little effect on protein production in NT2 stem cells. However, the neuronal cells showed a small increase in intracellular, KPI-containing APP and in HSP. A reduction in overall APP secretion, and cessation of KPI secretion accompanied this. To further investigate the effects of shock on APP production, mRNA levels in control and serum deprived NT2 and NT2N cells were studied using in situ hybridisation. Control NT2 cells contain low levels of APP751, APP695 and HSP mRNA, with higher levels of APP[770] mRNA. After serum deprivation HSP, APP[751] and APP[770] mRNA levels all rose significantly, while APP[695] mRNA levels were unchanged. Control NT2N cells contained high levels of APP695 mRNA, lower levels of APP[751] mRNA, and very low levels of APP[770] and HSP mRNA. Serum deprivation resulted in unchanged levels of APP[695] and APP[770] mRNA, while APP[751] and HSP levels were increased. These findings indicate that cellular stress can result in increased levels of APP, specifically APP[751], in both neuronal and non-neuronal cells. Increased levels of this isoform have also been reported in AD. Hence cellular stress leads to an increase in an APP isoform implicated in AD, and could also provide an explanation for the increased levels of betaA4 in the disease.
10

Sellstedt, Magnus. "Development of 2-Pyridone-based central fragments : Affecting the aggregation of amyloid proteins." Doctoral thesis, Umeå universitet, Kemiska institutionen, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-53705.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
There are many applications of small organic compounds, e.g. as drugs or as tools to study biological systems. Once a compound with interesting biological activity has been found, medicinal chemists typically synthesize small libraries of compounds with systematic differences to the initial “hit” compound. By screening the new ensemble of compounds for their ability to perturb the biological system, insights about the system can be gained. In the work presented here, various ways to synthesize small libraries of ring-fused 2‑pyridones have been developed. Members of this class of peptidomimetic compounds have previously been found to have a variety of biological activities, e.g. as antibacterial agents targeting virulence, and as inhibitors of the aggregation of Alzheimer b‑peptides. The focus in this work has been to alter the core skeleton, the central fragment, of the previously discovered biologically active 2‑pyridones and evaluate the biological effects of these changes. Several new classes of compounds have been constructed and their preparations have included the development of multi-component reactions and a method inspired by diversity-oriented synthesis. Some of the new compounds have been evaluated for their effect on the fibrillation of different amyloid proteins. Both the Parkinson-associated amyloid protein a-synuclein and the bacterial protein CsgA that is involved in bacterial biofilm formation are affected by subtle changes of the compounds’ central fragments. This is an example of the usefulness of central-fragment alterations as a strategy to probe structure-activity relationships, and the derived compounds may be used as tools in further study of the aggregation of amyloid proteins.
11

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.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
Une des caractéristiques histopathologiques de la maladie d'Alzheimer (AD) est la présence de plaques amyloïdes formées par les peptides amyloïdes β (Aβ) de 40 et 42 résidus, qui sont les produits de clivage par des protéases de l'APP. Afin de comprendre le rôle des variations structurelles du TM dans le traitement de l'APP, les peptides APP_TM4K ont été étudiés dans la bicouche lipidique en utilisant l’ATR-FTIR et ssNMR. Tandis que la structure secondaire globale du peptide APP_TM4K est hélicoidale, hétérogénéité de conformation et d'orientation a été observée pour le site de clivage γ et , que peuvent avoir des implications dans le mécanisme de clivage et donc dans la production d’Aβ. Les peptides Aβ s'agrègent pour produire des fibrilles et aussi de manière transitoire d'oligomères neurotoxiques. Nous avons constaté qu'en présence de Ca2+, l’Aβ (1-40) forme de préférence des oligomères, tandis qu'en absence de Ca2+ l'Aβ (1-40) s’agrège sous forme de fibrilles. 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. Ces résultats nous ont amené à conclure que les Ca2+ stimulent la formation d'oligomères d'Aβ (1-40), qui sont impliqués dans l’AD. Les positions et une orientation précise de deux nouveaux médicaments puissants modulateurs de la γ-sécrétase - le benzyl-carprofen et le sulfonyl-carprofen  dans la bicouche lipidique, ont été obtenus à partir des expériences des ssNMR. Ces résultats indiquent que le mécanisme probable de modulation du clivage par la y-sécrétase est une interaction directe avec le domaine TM de l’APP
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
12

Duggan, Claire. "The generation of the amyloid precursor protein intracellular domain." Thesis, University of Manchester, 2005. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:77486.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
Alzheimer's disease (AD) is the most common cause of a progressive decline of cognitive function in aged humans. It is thought to be a result of the formation of amyloid plaques in the brain that are largely composed of β-amyloid (Aβ), which is one of the cleavage products of the amyloid precursor protein (APP). The amyloidogenic processing of APP to produce the Aβ peptides requires sequential proteolytic cleavages by the β- and γ-secretases. APP is first cleaved by the β-secretase to produce APP-C99, and this product is a substrate for further processing by the γ-secretase that cleaves within its transmembrane domain to produce N-terminal Aβ peptides and the C-terminal APP intracellular domain (AICD). On the basis of similarities to the Notch processing pathway, it has been postulated that the AICD may play a role in gene regulation following its release in response to some form of extracellular signal. In order to better understand the production and fate of the AICD, I have investigated the potential for exploiting a cell-free system to study its generation and properties. Having generated a number of model APP-derived fragments and shown them to be efficiently membrane integrated in vitro, I went on to study AICD production. I discovered that AICD-like fragments are extremely labile when synthesised in a rabbit reticulocyte lysate system and are rapidly degraded via a metalloproteinase, most likely the insulin degrading enzyme (IDE). The in vitro stability of these model AICD-like fragments was dependent upon the precise chain length of the polypeptide and N-terminal processing may preface the activity of IDE in vitro. The rapid degradation of the AICD in vitro is in close agreement with previous in vivo studies, and taken together such data are consistent with a role for the AICD in a signalling pathway of some form. A variety of approaches were also taken to try to generate the AICD by the γ-secretase mediated cleavage of the APP-C99 fragment, a biologically relevant substrate. In no case was any evidence of such cleavage observed in vitro and hence I conclude that the endoplasmic reticulum does not possess an active form of the γ-secretase. Preliminary in vivo-based studies did provide evidence for the γ-secretase cleavage of APP-C99 fragments, consistent with current models implying that such processing takes place at the cell surface and/or in endosomes and not at the endoplasmic reticulum.
13

Stumm, Joachim. "Molekularbiologische und biochemische Charakterisierung von Transport, Prozessierung und Funktion des Amyloid-Vorläuferproteins (APP)." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=963140744.

Full text
APA, Harvard, Vancouver, ISO, and other styles
14

Crosier, Stephen. "Characterisation of a transgenic rat carrying the human amyloid precursor protein gene." Thesis, University of Newcastle upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245076.

Full text
APA, Harvard, Vancouver, ISO, and other styles
15

Hvoslef-Eide, Martha. "Characterising transgenic APP mutation mouse models of amyloid pathology for use in preclinical immunotherapy." Thesis, Cardiff University, 2012. http://orca.cf.ac.uk/43321/.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
No disease-modifying compounds are available to halt disease progression in Alzheimer’s disease (AD). Immunotherapy offers promising possibilities for the manipulation of Aβ levels which the amyloid cascade hypothesis proposes as the causative factor in AD. However, antiAβ antibodies have caused inflammation in vivo. An alternative antibody (2B3) which targets the β-secretase cleavage site of the amyloid precursor protein (APP) from which Aβ is cleaved has been shown to downregulate Aβ in human cell lines. The approach is thought unlikely to cause inflammation as the immune system is not relied upon for Aβ clearance. It was hypothesised that the administration of 2B3 to aged transgenic APP mutation mice would lower Aβ levels through the inhibition of Aβ production, with an associated lowering of cognitive deficits. Two murine APP mutation models [London APP(V717I) and Indiana PDAPP(V717F)] were characterised in order to identify cognitive deficits against which the ability of 2B3 to reduce deficits could be assessed. APP(V717I) mice were assessed in the marble burying task, the elevated plus maze and a foraging task assessing spatial working memory at 3, 6 and 19 months of age. The radial arm water maze was carried out at 10 months, before the T-maze non-matching to position task was administered at 11 months. Object recognition memory was assessed at 18 months. Similarly, PDAPP mice were assessed using the marble burying and elevated plus maze (9.5months), the T-maze (9-10 months), the foraging task (11 and 14 months) and the object recognition task (12 months). Whilst aged transgenic PDAPP mice displayed disrupted spatial working memory, no evidence of agerelated cognitive decline was observed in APP(V717I) transgenic mice despite increases in Aβ pathology with age. 2B3 did not alter Aβ levels or spatial working memory in PDAPP(V717F) mice in a pilot study, whilst the in vitro downregulation of Aβ was successfully replicated in primary murine neurons. The findings indicate that transgenic models of neurodegenerative disease require thorough characterisation to optimise their use in pre-clinical research. Furthermore, the use of alternative immunotherapy in the treatment of AD remains a promising, but early stage avenue of study.
16

Jacobsen, Kristin. "α-Secretase processing of the Alzheimer amyloid-β precursor protein and its homolog APLP2." Doctoral thesis, Stockholms universitet, Institutionen för neurokemi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-95114.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
The amyloid-β precursor protein (APP) has been widely studied due to its role in Alzheimer´s disease (AD). When APP is sequentially cleaved by β- and γ-secretase, amyloid-β (Aβ) is formed. Aβ is prone to aggregate and is toxic to neurons. However, the main processing pathway for APP involves initial cleavage at the α-site, within the Aβ region, instead generating a neuroprotective soluble fragment, sAPPα. APP is a member of a protein family, also including the proteins APLP1 and APLP2, which are processed in a similar way as APP. In addition, K/O studies in mice have shown that the three proteins have overlapping functions where APLP2 play a key physiological role. The aim of this thesis was to study mechanisms underlying the α-secretase processing of APP and APLP2. We have used the human neuroblastoma cell-line SH-SY5Y as a model system and stimulated α-secretase processing with insulin-like growth factor-1 (IGF-1) or retinoic acid (RA). Our results show that the stimulated α-site cleavage of APP and APLP2 is regulated by different signaling pathways and that the cleavage is mediated by different enzymes. APP was shown to be cleaved by ADAM10 in a PI3K-dependent manner, whereas APLP2 was cleaved by TACE in a PKC-dependent manner. We further show that protein levels and maturation of ADAM10 and TACE is increased in response to RA, mediated by a PI3K- or PKC-dependent signaling pathway, respectively. Another focus of our research has been O-GlcNAcylation, a dynamic post-translational modification regulated by the enzymes O-GlcNAc transferase and O-GlcNAcase (OGA). We show that decreased OGA activity stimulates sAPPα secretion, without affecting APLP2 processing. We further show that ADAM10 is O-GlcNAcylated. Lastly, we show that APP can be manipulated to be cleaved in a similar way as APLP2 during IGF-1 stimulation by substituting the E1 domain in APP with the E1 domain in APLP2. Together our results show distinct α-site processing mechanisms of APP and APLP2.

At the time of the doctoral defence the following papers were unpublished and had a status as follows: Paper 4: Manuscript; Paper 5: Manuscript.

17

Adlerz, Linda. "Processing of the amyloid precursor protein and its paralogues amyloid precursor-like proteins 1 and 2." Doctoral thesis, Stockholm : Department of Neurochemistry, Stockholm University, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-6763.

Full text
APA, Harvard, Vancouver, ISO, and other styles
18

Klein, Juliane. "Amyloid precursor protein (APP) and copper homeostasis in the human neuroblastoma cell line SH-SY5Y." Thesis, University of Newcastle upon Tyne, 2011. http://hdl.handle.net/10443/1201.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
Alzheimer’s disease (AD) is characterised by cerebellar accumulation and aggregation of amyloid beta (Aβ), a cleavage product of the transmembrane amyloid precursor protein (APP). APP contains a range of functional domains in its large extracellular portion, among which are two copper-binding motifs and one zinc-binding motif. The copper-binding motifs are present in the amino-terminal region of APP and within the Aβ region of the protein and readily reduce Cu(II) to Cu(I), thus APP and its cleavage products are linked to copper metabolism and have been hypothesised to participate in cellular copper homeostasis. In this project human neuroblastoma cell lines SH-SY5Y were utilised to determine the effect of expressing a familial AD mutation on intracellular copper concentrations and possible functional alterations or deficits of enzymes that require copper as a co-factor. The familial AD mutation first found in a Swedish population was previously shown to increase the total amount of released Aβ. Direct phenotypic comparison between SH-SY5Y APPWT cell lines expressing endogenous levels of APP and APPswe Coupling native two dimensional liquid chromatography with metal analysis, SDS-PAGE and Principal Component Analysis identified one major copper and zinc containing pool as copper-zinc superoxide dismutase (SOD1) in soluble whole cell protein extracts. Comparative analysis of metal content between APP cell lines overexpressing APP carrying the Swedish mutation was performed in standard culture and manipulated copper concentrations. WT and APPswe cultures indicated a difference in metallation of SOD1 with copper. APPswe cultures displayed reduced metallation of SOD1, whereas SOD1 metallation with zinc remained unaltered. Functional analysis of copper-binding enzymes, such as SOD1 and cytochrome c oxidase (CCO), using standard biochemical approaches, identified lower activities for both enzymes during standard cell culture in APPswe cells. Upon treatment of cultures with increasing concentrations of exogenous copper APPWT enzyme activities remained unaltered but enzyme activities in APPswe cultures increased in direct correlation with increasing copper concentrations. Combined with phenotypic analysis of growth, survival and intracellular metal content it appears that APPswe cultures are copper deficient, but this can be overcome by copper supplementation. Lower copper accumulation also enables greater survival of APP swe Overall, these data suggest that APP cells in elevated copper. swe overexpression in SH-SY5Y cells results in functional copper deficiency which can be rescued by supplementation of cultures with exogenous copper. APPswe further confers resistance to copper toxicity not only via increased Aβ release, but also via increased copper delivery to enzymatic target proteins improving cellular antioxidant response and energy metabolism. These data are consistent with a function of APP in copper efflux either in a regulatory capacity or directly contributing to copper egress.
19

Silva, Sílvia Isabel Ferreira da. "APP is a critical protein in spermatogenesis." Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/14858.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
Mestrado em Biomedicina Molecular
The Amyloid precursor protein (APP) and Tau protein are related to histopathological hallmarks of Alzheimer’s disease, a progressive and complex neurodegenerative disease. APP is a type 1 integral transmembrane glycoprotein. There are two predominant proteolytic processing pathways of APP, the nonamyloidogenic pathway, and the amyloidogenic pathway. Tau is one of the microtubule-associated proteins, and its binding affinity for microtubules is regulated by phosphorylation of serine and threonine residues. APP and Tau protein expression has also been reported in the testis. However, their function and posttranslational modifications in the testis have not been established. Thus, we analyzed the expression of these two proteins and their phosphorylation patterns during spermatogenesis using wild-type mice and rats as models. Through immunohistochemistry we revealed that APP, Tau protein, Serine/Threonine Protein Phosphatase (PP) 1α and PP1γ are expressed throughout spermatogenesis. APP and Tau are phosphorylated during meiosis. In contrast to total-APP localization, phosphorylated APP at Thr668 was specially localized in spermatocyte nuclei. These results suggest that phosphorylation of APP and Tau protein contribute to spermatogenesis, especially in meiosis. However, further research is required to validate our results and unravel the specific function of APP and Tau protein during spermatogenesis and meiosis.
A proteína precursora de amilóide (PPA) e a proteína Tau estão relacionadas com os marcos histológicos da doença de Alzheimer, uma doença neurodegenerativa progressiva e complexa. A PPA é uma glicoproteína integral transmembranar que tem duas predominantes vias de processamento proteolítico, a via não-amiloidogénica e a via amiloidogénica. A proteína Tau encontra-se associada aos microtúbulos, sendo a afinidade dessa ligação regulada pela fosforilação de resíduos de serina e treonina. A expressão da PPA e da proteína Tau também já foi reportada no testículo. No entanto, ainda não foram estabelecidas as suas funções e modificações pós-traducionais neste tecido. Assim, analisamos a expressão destas duas proteínas e o seu padrão de fosforilação durante a espermatogénese usando como modelos murganhos e ratos wild-type. Através de imuno-histoquímica revelamos que a PPA, a proteína Tau, a proteína serina/treonina fosfatase (PP) 1α e a PP1γ são expressas em toda a espermatogénese. Fosforilação da PPA e da proteína Tau foi detetada durante a meiose. Em contraste com a localização da PPA-total, a PPA fosforilada na treonina 668 está especialmente localizada no núcleo dos espermatócitos. Estes resultados sugerem que a fosforilação da PPA e da proteína Tau contribui para a espermatogénese, especialmente na meiose. No entanto, são necessários estudos futuros para validar os nossos resultados e desvendar a função específica da PPA e da proteína Tau durante a espermatogénese e na meiose.
20

Edblom, Sara. "A Comparison of Two Immunoturbidimetric Assay Methods for Serum Amyloid A in Cats." Thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-154803.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
The analysis of acute phase protein serum amyloid A (SAA) has recently been brought into clinical use in veterinary medicine. Some of the difficulties with incorporating the SAA method in clinical practice have been the expensive and rather large equipment required for the method. Due to these difficulties only larger clinics can afford to use the SAA analysis. The company Equinostic has recently developed a smaller instrument that costs one-tenth of a larger instrument. The instrument is named EVA1 and has so far only been used to analyze SAA in horses. The aim of this study was to investigate if the EVA1 instrument could be used to analyze SAA in cats. This study included 24 serum samples from cat, which were first analyzed twice on the EVA1 instrument and then sent to the Strömsholm Referral Animal Hospital in Sweden where they reanalyzed the samples using a validated reference method. Both instruments are based on an immunoturbidimetric assay. The correlation between the two instruments was good (r=0.97) but the EVA1 instrument showed constantly lower results than the reference method. The difference between the duplicates when analyzed on the EVA1 instrument was larger than expected. The conclusion is that EVA1 could be used to analyze SAA in cats. However, before it could be used clinically in veterinary practice an extended study is recommended.
21

Chan, Lai Ling Sharon Medical Sciences Faculty of Medicine UNSW. "The potential function of ATP-binding cassette A7 in the brain: implications for Alzheimer's disease." Publisher:University of New South Wales. Medical Sciences, 2009. http://handle.unsw.edu.au/1959.4/44409.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
ABCA7 is the closest homologue of ABCA1, which is established to play a key role in reverse cholesterol transport. ABCA1 deficiency causes Tangier disease and several ABCA1 modulations have been recently associated with Alzheimer’s disease. Prior research on ABCA7 focused on its role in macrophage lipid efflux and phagocytosis, however, tissue expression studies in mice revealed that ABCA7 is highly expressed in the brain. The function of ABCA7 in the brain is unknown and the purpose of this thesis was therefore to investigate the potential function of ABCA7 in the brain and the possible implications for Alzheimer’s disease. This was achieved by using in vitro models that transiently express ABCA7 and in vivo models including ABCA7 knockout (ABCA7 KO) mice and human APP transgenic (APPSwInd Tg) mice. ABCA7 was shown to potently stimulate cholesterol efflux from cells to extracellular apoE acceptors. Additionally, apoE expression was decreased by 20% in the brains of ABCA7 KO mice compared to wild type littermate controls and by 46% in ABCA7-deficient macrophages. In vitro models that stably express human APP protein demonstrated that the transient expression of ABCA7 increased intracellular APP targeting, which led to the inhibition of APP processing and a resultant decrease in the production of Aβ. In addition, ABCA7-deficient macrophages displayed impaired capacity to endocytose and degrade Aβ oligomers. Finally, in aged APPSwInd Tg mice where abundant amyloid plaques were present, ABCA7 expression was significantly decreased by 48%. Since cholesterol homeostasis modulates APP processing, the findings of this thesis suggest that ABCA7 may have a role in maintaining cellular cholesterol homeostasis via cholesterol efflux to apoE acceptors and possibly by regulating intracellular trafficking of specific membrane proteins. In summary, ABCA7 was clearly shown in this thesis to have an effect on Aβ generation, clearance and degradation. Furthermore, ABCA7 expression was also affected by Aβ deposition in the brain. Even though more work is required to further elucidate the exact function of ABCA7, the findings presented in this thesis provide the first clues to the function of ABCA7 in the brain.
22

Chiocco, Matthew J. "Beta-Secretase Trangenic Mice: Effects of BACE1 and BACE2 on Alzheimer's Disease Pathogenesis." Case Western Reserve University School of Graduate Studies / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=case1111597750.

Full text
APA, Harvard, Vancouver, ISO, and other styles
23

CATANIA, MARCELLA. "Anti-amyloidogenicactivity of a mutant form of Aβ: a new strategy for Alzheimer therapy." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2012. http://hdl.handle.net/10281/29859.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
Amyloid-β precursor protein (APP) mutations cause familial Alzheimer’s disease with virtually complete penetrance. We found an APP mutation (A673V) that causes disease only in the homozygous state, while heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced amyloid β (Aβ) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Aβ aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance, and have implications for genetic screening and the potential treatment of Alzheimer’s disease.
24

Schreiber, Arne [Verfasser]. "Bildungsmechanismus und physiologische Relevanz supramolekularer Proteincluster des Amyloid Precursor Protein APP in der Zellmembran / Arne Schreiber." Bonn : Universitäts- und Landesbibliothek Bonn, 2013. http://d-nb.info/104486785X/34.

Full text
APA, Harvard, Vancouver, ISO, and other styles
25

Mensch, Maria. "Étude du rôle pathophysiologique des peptides Aη récemment découverts dans le cerveau." Electronic Thesis or Diss., Université Côte d'Azur, 2020. http://theses.univ-cotedazur.fr/2020COAZ6001.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
L’implication de la protéine précurseur de l’Amyloïde (APP) est bien établie dans la pathologie Alzheimer, une des maladies neurodégénératives la plus étendue à travers le monde. Ces 30 dernières années de nombreuses études focalisent sur cette pathologie mais le progrès dans la compréhension de son étiologie et les cures possibles restent cependant limitées. Toutes les études concernant la forme familiale et les cibles potentielles, soulignent l’importance d’APP et des fragments issus de son clivage. Déchiffrer le rôle des différents fragments d’APP dans la fonction synaptique et leurs effets comportementaux est crucial dans la compréhension de l’étiologie de cette pathologie. En 2015, Willem et al, ont décrit une nouvelle voie de clivage produisant le peptide Amyloid-η (Aη). Ils ont pu démontrer que le peptide Aη−α, dans sa forme la plus longue, produit par le clivage de l’η-secretase et α-secretase, alimente des propriétés bioactives. Appliqué dans l’hippocampe ex vivo, il diminue la potentialisation à long terme (PLT) et in vivo il réduit les ondes calciques. Au-delà de ces observations initiales, ma thèse intitulée « Étude du rôle pathophysiologique des peptides Aη récemment découverts dans le cerveau » focalise sur le rôle d’Aη dans différents paramètres de la plasticité synaptique excitatrice et les comportements associés. Nous avons testé les effets d’une augmentation aigue et chronique d’Aƞ-α, en administrant de l’Aη-α synthétique (M108) de manière aigue sur des tranches d’hippocampe ex vivo et via l’analyse de nouvelles lignées de souris transgéniques MISEPA2 et MISEPA4 sur-exprimant l’Aη-α. Nos résultats montrent l’impact d’Aη-α sur la plasticité synaptique à des concentrations nano-molaires en induisant une dépression à long terme (DLT), tandis que la plasticité présynaptique à court terme et la transmission synaptique basale sont inchangées. Puis, afin d’élucider les effets aigus et chroniques d’un taux élevé d’Aη-α sur la cognition, nous avons mené une série de tests mnésiques. L’analyse des lignées transgéniques révèlent aucun déficit majeur de mémoire, bien que des altérations subtiles soient notables lors d’analyses individuelles. De plus des injections intracérébrales aigues de M108 chez des souris in vivo ne montrent pas de déficit de mémoire. Nous concluons que, bien que la plasticité synaptique excitatrice hippocampique soit clairement impactée par des taux élevés d’Aη-α, aucun phénotype comportemental majeur ne semble apparent. En parallèle, nous avons étudié la plasticité synaptique et le comportement dans un nouveau modèle de souris Knock-out APPΔEta, dans lequel le clivage d’APP par la η-secretase est absent. Dans cette lignée la DLT ne peut pas être induite, mais l’application aigue de M108 rétablit la DLT. Ces données révèlent donc un rôle crucial de l’Aη-α dans ce mécanisme de plasticité synaptique. De plus, les souris APPΔEta montrent un déficit en mémoire spatiale dans le test de la piscine de Morris et une baisse de l’anxiété dans le test d’openfield et les boites claires obscures, indiquant que le clivage d’APP par η-secretase est nécessaire dans les fonctions cognitives. En conclusion, nos résultats contribuent à la compréhension du rôle d’Aη-α dans la physiopathologie, mettant en avant son rôle essentiel dans la plasticité synaptique et la cognition
The amyloid precursor protein (APP) is well known by its association with Alzheimer's disease (AD), the most common neurodegenerative disease worldwide. Despite intense research focusing on AD over the last 30 years, the progress in understanding its etiology and finding a cure has been limited. Thus far, all data gathered regarding the genetic causes of familiar AD, the progression of the disease, and potential therapeutic targets for AD, highlight the importance of APP and its cleavage products. Deciphering the role of the different APP fragments in synaptic function and behavior is crucial to understand AD etiology fully. In 2015, Willem et al., described a new APP processing pathway producing amyloid-η (Aη) peptides. They could demonstrate that the Aη-α peptide, the longest form of Aη produced by η-secretase and α-secretase cleavage, harbors bioactive properties. Applied on the hippocampus ex vivo it lowers long-term potentiation (LTP) and in vivo it lowers calcium wave activity. Going beyond these initial observations, my thesis, "Unraveling the physiopathological role of the newly discovered Aη peptides in the brain" focused on further identifying Aƞ-α actions on different parameters of excitatory synaptic plasticity and associated behavioral outputs. We tested the effects of acute and chronic elevations of Aƞ-α, employing acute application of synthetic Aƞ-α (M108) on hippocampal slices ex vivo or via the analysis of new transgenic mouse lines MISEPA2 and MISEPA4 overexpressing Aƞ-α, respectively. Our results show that Aη-α impacts synaptic plasticity at low nanomolar concentrations and shifts plasticity towards long-term depression (LTD), while it does not perturb pre-synaptic short-term plasticity or basal synaptic transmission. Next, to unravel the effects of both acute and chronic elevated Aƞ-α levels on cognition, we performed a series of memory-dependent behavioral tests. Analysis of the transgenic mouse lines indicated no major memory impairments, although subtle alterations were noticeable upon individual testing and analysis paradigms. Also, an acute injection of M108 in the brain in vivo did not correlate with significant memory loss. We conclude that, while hippocampal excitatory synaptic plasticity is clearly impacted by elevated Aη-α levels, this cellular phenotype failed to robustly translate into alterations of behavioral output thus far. In parallel, we went on to investigate the effects on synaptic plasticity and behavior caused by the absence of APP processed by ƞ-secretase in a novel knock-out APPΔEta mice line. In this mouse line LTD could not be induced, but acute M108 application rescued this phenotype. These data reveal a crucial role of Aη-α in this synaptic plasticity mechanism. Additionally, APPΔEta mice exhibited impaired spatial memory in MWM task and reduced anxiety in the Open field and Light-Dark box tests, indicating that this APP cleavage is necessary for cognitive functions. In conclusion, our results advanced the understanding of the physio-pathological role of Aƞ in the brain, highlighting an essential function in excitatory synaptic plasticity and cognition
26

Rijal, Upadhaya Ajeet [Verfasser]. "Analysis of Amyloid beta (Aβ) protein in Amyloid precursor protein (APP) transgenic mouse models of Alzheimer’s disease (AD) and in human brains / Ajeet Rijal Upadhaya." Ulm : Universität Ulm. Medizinische Fakultät, 2012. http://d-nb.info/1025715012/34.

Full text
APA, Harvard, Vancouver, ISO, and other styles
27

Kendal, Claire. "The influence of the deletion and overexpression of APP in transgenic mice on the morphology of the dentate gyrus." Thesis, Open University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340742.

Full text
APA, Harvard, Vancouver, ISO, and other styles
28

Lindström, Elin. "Quantifying soluble isoforms of amyloid precursor protein in cerebrospinal fluid with a SRM-MS based assay ─ method development." Thesis, Linköpings universitet, Institutionen för fysik, kemi och biologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-89992.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
Alzheimer’s is a widespread neurodegenerative disease, growing larger and larger in the world. Once developed, the disease has no cure. To this day, there is only mitigating drugs. To be able to start this treatment rapidly, a method to distinguish healthy individuals from prospective Alzheimer’s diseased needs to be developed. Cerebrospinal fluid is thought to contribute to the development of such method, through its close substitution of fluids, molecules and proteins from the brain. It may provide a progressive marker of the disease, a substance differently expressed in the healthy and diseased; a biomarker. The aim of the present study was to develop and evaluate a stable method for degradation and analysis of peptides and proteins in the cerebrospinal fluid using mass spectrometry techniques, such as selective reaction monitoring. Mass spectrometry is often used after a first dimension separation with liquid chromatography. Three degradation methods were evaluated, resulting in a protocol with the detergent DOC being the most beneficial. Tryptic peptides occurred in a concentration of 10 % w/v due to the SDS-PAGE gels and database searches concomitantly. The elution pattern from the liquid chromatography enables a narrow selection in the sensitivity for each peptide. Chromatographic preferences such as column, hydrophobicity and time span was determined, and unwanted peptides filtered away. A specific protein, the amyloid precursor protein APP, is thought to play a significant part in the development of Alzheimer’s disease. The protein is located in the neurons, cleaved and processed to produce the neurodegenerating plaques found in the brain at the diseased. Three isoforms are found in the neurons, APP695, APP751 and APP770. When cleaved, a shorter soluble tryptic peptide is generated from all APP isoforms. This was the target for the current study, as a potential progressive biomarker. The method developed was able to separate and distinguish the soluble APP751 isoform, but not the APP695 or APP 770 isoforms, most probably due to glycosylations of the two resembling isoforms.
29

Kernekewisch, Michaela. "Untersuchungen zur Expression des interzellulären Adhäsionsmoleküls ICAM-1 und zur Prozessierung des Amyloid-Vorläuferproteins APP in Astrozyten." [S.l.] : [s.n.], 1998. http://deposit.ddb.de/cgi-bin/dokserv?idn=956666450.

Full text
APA, Harvard, Vancouver, ISO, and other styles
30

Isbert, Simone [Verfasser]. "Cellular localization and mechanism of amyloid precursor protein (APP) homodimer formation in an oxidizing environment / Simone Isbert." Mainz : Universitätsbibliothek Mainz, 2012. http://d-nb.info/1020164611/34.

Full text
APA, Harvard, Vancouver, ISO, and other styles
31

El, Hajj Hassan. "Spatial heterogeneity in microglial ultrastructural alterations in the APP-PS1 mouse model of Alzheimer's disease amyloid pathology." Master's thesis, Université Laval, 2019. http://hdl.handle.net/20.500.11794/35424.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
Les principales caractéristiques de la maladie d'Alzheimer (MA) sont le dépôt de plaques amyloïdes (Aβ) extracellulaires et les enchevêtrements neurofibrillaires intracellulaires composés de protéines tau. À mesure que la maladie progresse, la mort neuronale et une diminution de la densité synaptique sont observées, parallèlement à une augmentation de la neuroinflammation et du dysfonctionnement immunitaire. Le processus de neuroinflammation est étroitement lié à la présence de plaques Aβ et peut affecter les interactions microgliales avec les structures neuronales tout au long de la progression de la maladie. L'activation substantielle et chronique des microglies déclenchée par la présence d'Aβ est supposée affecter l'homéostasie cérébrale en raison d'une altération des actions physiologiques microgliales, notamment au niveau des synapses. Ici, nous visons à générer de nouvelles connaissances sur l'implication microgliale dans la physiopathologie de la MA en combinant la microscopie optique et électronique pour étudier l'ultrastructure microgliale et les interactions neuronales / synaptiques en relation avec le dépôt de plaques Aβ. Des souris APP-PS1 âgées de 14 mois ont été étudiées en même temps que des témoins appariés selon l'âge. En outre, des sections de la MA humaine post-mortem ont également été examinées dans notre étude. Dans nos expériences, les plaques Aβ ont été visualisées en utilisant du méthoxy-XO4 qui se lie sélectivement et irréversiblement aux feuilles d'Aβ et permet leur détection en microscopie optique. De plus, l'immunocoloration post-mortem de la microglie avec le marqueur de la molécule adaptatrice de fixation du calcium ionisée (IBA1) et un traitement supplémentaire pour la microscopie électronique à transmission ont permis d'étudier la microglie à différentes proximités des plaques. Nos analyses ultrastructurelles ont révélé des différences significatives dans les activités phagocytaires et les caractéristiques morphologiques. Les corps cellulaires microgliaux de l'APP-PS1 avaient une surface et un périmètre significativement supérieurs à ceux des témoins de type sauvage et présentaient des signes de stress et une activité phagocytaire diminuée. Ces signes de stress et de phagocytose altérée ont également été observés dans les prolongements microgliaux des échantillons APP-PS1. De plus, les microglies présentaient divers phénotypes morphologiques et réactions cellulaires physiologiques selon leur proximité des plaques. Les corps des cellules microgliales proches des plaques étaient plus larges en surface et en périmètre que les témoins de type sauvage et les autres régions APPPS1 situées plus loin des plaques. Les microglies proches des plaques étaient plus susceptibles de contenir des dépôts Aβ et moins susceptibles de contenir ou d’encercler des éléments neuronaux. En outre, elles présentaient des signes de stress caractérisés par des corps cellulaires assombris et un réticulum endoplasmique dilaté. Tous ces résultats définissent les changements radicaux qui se produisent au niveau ultrastructural dans le cerveau en réponse à la déposition Aβ
The main hallmarks of Alzheimer’s disease (AD) are the deposition of extracellular amyloid (A)β plaques and intracellular neurofibrillary tangles composed of tau protein. As the disease progresses, neuronal death and decreased synaptic density is observed, concurrent with an increase of neuroinflammation and immune dysfunction. The process of neuroinflammation is tightly linked to the presence of Aβ plaques and may affect microglial interactions with neuronal structures throughout disease progression. Substantial and chronic microglial activation triggered by the presence of Aβ is suspected to affect brain homeostasis due to an alteration of microglial physiological actions, notably at synapses. Here we aim to generate new insights regarding microglial implication in AD pathophysiology by combining light and electron microscopy to study microglial ultrastructure and neuronal/synaptic interactions with relation to Aβ plaque deposition. 14 months old APP-PS1 mice were studied alongside age-matched controls. Also, postmortem human AD sections were examined in our study. In our experiments, Aβ plaques were visualized using Methoxy-XO4 which binds selectively and irreversibly to Aβ sheets and allows their detection under light microscopy. Furthermore, post-mortem immunostaining of microglia with the ionized calcium-binding adapter molecule 1 (IBA1) marker and additional processing for transmission electron microscopy allowed the study of microglia at different proximities to the plaques. Our ultrastructural analyses revealed significant differences in phagocytic activities and morphological features. Microglial cell bodies in APP-PS1 were significantly larger in area and perimeter compared to wild-type controls and displayed signs of stress and decreased phagocytic activity. These signs of stress and impaired phagocytosis were also found in microglial processes in the APP-PS1 samples. Additionally, microglia showed diverse morphological phenotypes and physiological cell reactions dependent on their proximity to plaques. Microglial cell bodies near plaques were larger in area and perimeter compared to wild-type controls and other APP-PS1 regions located farther from plaques. Microglia near plaques were more were more likely to contain Aβ and less likely to contain or encircle neuronal elements. Also, they presented signs of stress characterized by darkened cell bodies and dilated endoplasmic reticulum. All these findings define the drastic changes that are taking place at ultrastructural level in the brain in response to Aβ deposition.
32

Yamada, Mahito. "The Influence of Chronic Cerebral Hypoperfusion on Cognitive Function and Amyloid β Metabolism in APP Overexpressing Mice." Kyoto University, 2011. http://hdl.handle.net/2433/142093.

Full text
APA, Harvard, Vancouver, ISO, and other styles
33

Kernekewisch, Michaela. "Untersuchungen zur Expression des interzellulären Adhäsionsmoleküls ICAM-1 und zur Prozessierung des Amyloid-Vorläuferproteins APP in Astrozyten." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 1998. http://dx.doi.org/10.18452/14324.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
Neben aktivierten Astrozyten weisen zahlreiche Zytokine und Wachstumsfaktoren, die in der Nähe amyloidogener Ablagerungen im Hirn des Alzheimer-Patienten auftreten, auf eine Alzheimer-assoziierte Neuroinflammation hin, die an der Ausprägung der Neurodegeneration ursächlich beteiligt sein kann. Bisher ist die Bedeutung aktivierter Astrozyten für die Alzheimer-Pathogenese wenig untersucht worden. Von besonderem Interesse war in diesem Zusammenhang das interzelluläre Adhäsionsmolekül ICAM-1, da es mit amyloidogenen Ablagerungen und Astrozyten assoziiert vorliegt. Um einen ersten Hinweis auf eine mögliche pathophysiologische Rolle des ICAM-1 in der Alzheimer-assoziierten Neuroinflammation zu erhalten, wurde im ersten Teil der vorliegenden Arbeit die astrozytäre ICAM-1-Expression in Abhängigkeit unterschiedlicher Mitogene untersucht, die für die Alzheimer-Pathogenese von Bedeutung sind. Aus diesen Untersuchungen ging hervor, daß Astrozyten, die mit den Zytokinen IL1[beta], TNF[alpha] und TNF[alpha] mit IFN[gamma] behandelt wurden, ihre ICAM-1-Expression verstärkten. Es konnte erstmals gezeigt werden, daß eine Erhöhung der intrazellulären cAMP-Konzentration durch Forskolin, Rolipram und Prostglandine die Zytokin-verstärkte ICAM-1-Expression verminderte. Allerdings konnte eine schon bestehende astrozytäre Aktivität durch cAMP-erhöhende Substanzen nicht beeinflußt werden. Im Rahmen weiterer Untersuchungen wurde in dieser Arbeit gezeigt, daß die astrozytäre ICAM-1-Expression nicht durch das Amyloid[beta]-Protein ausgelöst oder verstärkt wird, dagegen konditionierte Medienüberstände A[beta]-aktivierter Mikroglia einen starken Einfluß auf die astrozytäre Aktivität ausüben. Im zweiten Teil dieser Arbeit ist die Untersuchung aktivierter Astrozyten in der Alzheimer-assoziierten Amyloidogenese beschrieben, die im Zusammenhang mit der amyloidogenen Prozessierung des Amyloid-Vorläuferproteins APP steht. Bisher standen Neurone als Hauptproduzenten des Amyloid [beta]-Proteins im Vordergrund der Alzheimer-Forschung. Da jedoch verschiedene Veröffentlichungen darauf hinweisen, daß Astrozyten ebenfalls eine direkte Rolle in der Entstehung der amyloidogenen Ablagerungen spielen können, wurde die amyloidogene APP-Prozessierung aktivierter Astrozyten untersucht. Neben vergleichenden Analysen der astrozytären und neuronalen APP-Prozessierung konnte im Rahmen dieser Arbeit erstmals gezeigt werden, daß sich die APP-Prozessierung aktivierter Astrozyten zugunsten des nicht-amyloidogenen Prozessierungsweges verlagert, d.h. aktivierte Astrozyten verringerten die Sekretion des A[beta]-Proteins. Ein charakteristisches Merkmal aktivierter Astrozyten ist eine verstärkte [alpha]-Sekretaseaktivität bei der APP-Prozessierung. Astrozyten, die mit den Zytokinen IL1[beta], TNF[alpha] und TNF[alpha] mit IFN[gamma] aktiviert wurden, akkumulierten nicht-amyloidogene C-terminale Fragmente, sekretierten verstärkt sekretorisches APP nach [alpha]-Sekretaseaktivität und zeigten eine verringerte A[beta]-Sekretion bei gleichzeitig verstärkter Sekretion des nicht-amyloidogenen p3-Fragmentes. Abschließend wurde die pathophysiologische Bedeutung der Astrozyten in der Alzheimer-Pathogenese im Zusammenhang mit den erzielten Ergebnissen aus dieser Arbeit und mit den Befunden anderer Forschungsgruppen diskutiert und ein Modell über die zellulären, neuroinflammatorischen Vorgänge in der Alzheimer-Pathogenese entwickelt.
Activated astrocytes, number of cytokines and growth factors are associated with amyloidogenic deposits in the brain of Alzheimer-patients, pointed to an Alzheimer-associated neuroinflammation, that could be involved in the progression of the neurodegeneration. So far the implication of activated astrocytes in the pathogenesis of Alzheimer's disease is not clear. In this connection the adhesion molecule ICAM-1 was of particularly interest, because it is associated with astrocytes and amyloidogenic deposits. To get insights in a possible pathophysiological role of ICAM-1 in the Alzheimer-associated neuroinflammation, in the first part of this thesis the astrocytic expression of ICAM-1 was investigated dependent on different mitogens, that are relevant to the pathogenesis of Alzheimer's disease. It was shown that the expression of ICAM-1 was enhanced in astrocytes treated with the cytokines IL1[beta], TNF[alpha] and the combination TNF[alpha] with IFN[gamma]. It was shown that an elevation of intracellular concentration of cAMP by forskolin, rolipram and prostaglandines results in an suppressed cytokine-stimulated ICAM-1 expression. But it was impossible to reduce an existing astrocytic activity by these cAMP-elevating agents. Within the scope of additional investigations it was shown that the expression of ICAM-1 was not induce by the amyloid [beta]-peptide, whereas the ICAM-1 expression was strongly enhanced by conditioned media of A[beta]-activated microglia. In the second part of this thesis the investigation of activated astrocytes in the Alzheimer-associated amyloidogenesis is described, the astrocytic processing of the amyloid precursor protein (APP). So far it is believed that the neurons are the main producers of the amyloid [beta]-peptide. But different publications pointed to the possibility that astrocytes could play a direct role in the generation of the amyloidogenic deposits. From this reason the amyloidogenic processing of APP was investigated in activated astrocytes. Besides comparative study of astrocytic and neuronal APP processing it was first shown that activated astrocytes practise more the non-amyloidogenic pathway of APP processing. A characteristic hallmark of activated astrocytes is an increased activity of [alpha]-secretase. Astrocytes that are activated by the cytokines IL1[beta], TNF[alpha] or TNF[alpha] with IFN[gamma] showed an accumulation of non-amyloidogenic C-terminal fragments, increased APP-secretion followed by [alpha]-secretase activity, decreased A[beta]-secretion and enhanced p3-secretion. In conclusion the pathophysiological role of astrocytes in the pathogenesis of Alzheimer's disease was discussed leading to a model of cellular neuroinflammatory events in the pathogenesis of Alzheimer's disease.
34

Bastos, Luísa Filipe Henriques Martins de. "Unraveling the APP/HB-EGF interaction." Master's thesis, Universidade de Aveiro, 2013. http://hdl.handle.net/10773/12503.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
Mestrado em Biomedicina Molecular
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide and the leading cause of dementia in the elderly. Abnormal processing of Alzheimer’s amyloid precursor protein (APP) and increased generation of its amyloid beta (Aβ) fragment are central events in the AD pathogenesis, propelling major studies on APP biology. APP is thought to be involved in important processes such as cell adhesion, survival, migration and differentiation. Therefore, because of the imperative need to study APP biological functions, the search for APP-binding partners has stand out. Recently in our laboratory, a plethora of putative APP-binding proteins was unraveled through the use of the Yeast Two Hybrid (YTH) system. Among them, the heparin-binding epidermal growth factor-like growth factor (HB-EGF) has emerged as an interesting target of study. HB-EGF is a heparin-binding member of the EGF family of growth factors that stimulates growth and differentiation. It has been purposed has an important trophic factor in the developing and adult central nervous system (CNS), being expressed at much higher levels than EGF in the CNS, which indicates that HB-EGF may serve as a major ligand for EGFR in neurons. HB-EGF is synthesized as a pre-pro-form of 208 amino acids in length and is expressed at the cell surface as a 20-30kDa type I transmembrane precursor, named proHB-EGF. This larger membrane-anchored precursor is then proteolytically processed, generating the mature soluble HB-EGF (sHB-EGF) that is released to the extracellular medium. Very interestingly, HB-EGF presents autocrine, paracrine and juxtacrine biological activities, with proHB-EGF evidencing unique biological characteristics distinct from sHB-EGF. In the work here described, we first validated the APP/HB-EGF interaction by yeast co-transformation, and unraveled that the interaction is not mediated by the APP intracellular domain (AICD). We further confirmed it as an in vivo interaction by GFP-Trap pull-down assays and accessed the physiological relevance of this novel interaction through co-localization and signaling studies in HeLa cells transfected with the APP-GFP and HB-EGF cDNAs. Although the functional role of the APP/HB-EGF complex was not determined, results suggest that these proteins physically and functionally interact, having potential value in regulating each other signal pathways, with a role for APP in inducing the activation of the MAPK signaling being evidenced. In addition, a putative novel interaction with a proEGF species was also detected and APP was shown to act synergistically with EGF to activate the MAPK signaling. These results deepen our understanding of the APP biology, a crucial protein in cerebral physiology and AD pathophysiology.
A Doença de Alzheimer (DA) é a doença neurodegenerativa mais prevalente a nível mundial, e a principal causa de demência na população sénior. O processamento anormal da Proteína Precursora de Amilóide de Alzheimer (PPA) e a produção aumentada do seu fragmento beta amilóide (Aβ) constituem eventos centrais na patogénese da DA, o que tem fomentado a investigação da PPA. Esta tem sido descrita como uma proteína envolvida em processos celulares determinantes, como adesão, migração, diferenciação, e sobrevivência celular. Como tal, devido à necessidade imperativa de caracterizar as suas funções biológicas, a investigação de proteínas que interagem com a PPA é de vital importância. Recentemente, diversas proteínas foram identificadas no nosso laboratório como putativos interatores da PPA, através da técnica de Yeast Two Hybrid (YTH). De entre estes, o fator de crescimento de ligação à heparina semelhante ao fator de crescimento epidermal (HB-EGF) revelou-se um interessante alvo de estudo. O HB-EGF é um membro da família do fator de crescimento epidermal (EGF) com capacidade de ligação à heparina, que se destaca pelas suas capacidades de estimular o crescimento e diferenciação celulares, tendo sido proposto como um relevante fator trófico para o desenvolvimento e manutenção do sistema nervoso central (SNC). Na verdade, o HB-EGF é mais abundante no SNC do que o próprio EGF, o que sugere que o HB-EGF é o principal ligando neuronal para o recetor do EGF (EGFR). O HB-EGF é sintetizado como um precursor de 208 aminoácidos (pre-proHB-EGF), sendo exposto na membrana celular como um precursor transmembranar de 20-30 kDa, o proHB-EGF. Esta forma é subsequentemente proteoliticamente processada, gerando um péptido solúvel que é libertado para o meio extracelular (sHB-EGF). Curiosamente, o HB-EGF apresenta atividades biológicas parácrinas, autócrinas e justácrinas. O presente trabalho teve como principal objetivo a validação da interação entre a PPA e o HB-EGF, primeiramente alcançado através da técnica de YTH, que revelou também que a interação entre as duas proteínas não é mediada pelo domínio intracelular da PPA. Esta interação foi subsequentemente confirmada por ensaios de GFP-Trap pull-down em cultura de células de mamífero, e a sua relevância fisiológica estudada através de estudos de co-localização e sinalização celulares, usando células HeLa transfectadas com os cDNAs da PPA e do HB-EGF. Apesar do papel funcional do complexo PPA/HB-EGF não ter sido determinado, os resultados obtidos sugerem que as duas proteínas interagem física e funcionalmente, influenciando a sinalização mediada por cada uma delas separadamente, como a ativação da via de sinalização MAPK que verificámos ser também induzida pela PPA. Adicionalmente, descrevemos uma nova interação proteica entre a PPA e uma forma precursora do EGF, e demonstrámos que a PPA atua de forma sinérgica com o EGF. Estes resultados levam a uma maior compreensão da biologia da PPA, uma proteína importante na fisiologia cerebral e na fisiopatologia da DA.
35

Vrotsos, Emmanuel George. "MCP-1 and APP involvement in glial differentiation and migration of neuroprogenitor cells." Orlando, Fla. : University of Central Florida, 2009. http://purl.fcla.edu/fcla/etd/CFE0002517.

Full text
APA, Harvard, Vancouver, ISO, and other styles
36

Anni, Daniela [Verfasser], Anna [Akademischer Betreuer] Fejtová, and Johann Helmut [Gutachter] Brandstätter. "Regulation of presynaptic plasticity by APP/Aβ-derived fragments / Daniela Anni ; Gutachter: Johann Helmut Brandstätter ; Betreuer: Anna Fejtová." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2021. http://d-nb.info/1235224562/34.

Full text
APA, Harvard, Vancouver, ISO, and other styles
37

Liang, Binhua. "Molecular cloning and sequence analysis of a human brain cDNA of an Alzheimer amyloid precursor (APP) interacting protein." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0004/MQ45086.pdf.

Full text
APA, Harvard, Vancouver, ISO, and other styles
38

Noda, Yasuha. "Fibronectin type III domain-containing protein 5 interacts with APP and decreases amyloid β production in Alzheimer’s disease." Kyoto University, 2019. http://hdl.handle.net/2433/236620.

Full text
APA, Harvard, Vancouver, ISO, and other styles
39

Rezai-Zadeh, Kavon. "Flavonoids as Modulators of Amyloid Precursor Protein Metabolism and Alzheimer Disease Pathology." [Tampa, Fla] : University of South Florida, 2008. http://purl.fcla.edu/usf/dc/et/SFE0002683.

Full text
APA, Harvard, Vancouver, ISO, and other styles
40

THERIN, SEBASTIEN. "USE OF A CELL PERMEABLE PEPTIDE TO MODULATE ADAM10 SYNAPTIC LOCALIZATION AND ACTIVITY IN A MOUSE MODEL OF ALZHEIMER'S DISEASE." Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/649095.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:
Alzheimer’s disease (AD) is characterized by the aggregation of amyloid beta peptide (Aβ). Aβ derives from the amyloid precursor protein (APP), which can undergo two mutually exclusive pathways. The amyloidogenic pathway involves BACE and γ-secretase activities and leads to Aβ formation. While, the non-amyloidogenic pathway involves ADAM10, a disintegrin and metalloproteinase 10, which cleaves APP within the domain corresponding to Aβ, thus precluding Aβ production. Recently, we identified a new ADAM10 binding partner, named AP2, which is responsible for ADAM10 internalization, therefore affecting its activity. Interestingly, ADAM10/AP2 interaction is significantly increased in AD patients' brain compared to healthy control subjects, suggesting a role of ADAM10/AP2 in AD pathogenesis. In this framework, we have recently developed a cell permeable peptide (named PEP3) capable of interfering with ADAM10/AP2 association. The intraperitoneal administration of this CPP to a mouse model of AD for two weeks is safe and effective in impairing ADAM10 endocytosis and, thereby, in increasing ADAM10 synaptic localization. At late stages of disease, the PEP3 administration is able to change biochemical parameters, as Aβ levels and the molecular composition of the synapses without ameliorating the cognitive deficits of these mice. On the other hand, at early stage of the pathology the 14-days administration of the PEP3 rescues the cognitive impairment of the AD mice. Further investigations revealed that the synaptic levels of the NMDA receptor subunit GluN2A are increased upon the treatment and that previously observed shrinkage and dendritic spine loss in AD mice were improved after CPP treatment. These results are mediated by an increase in endogenous sAPPα. These positive results point to ADAM10 internalization as a potential target mechanism for the development of an effective AD therapy.
41

Krämer, Lara Maria [Verfasser]. "Inclusions of N-terminal fragments of APP in basophilic degeneration of cardiomyocytes: Pathological and clinical impact / Lara Maria Krämer." Ulm : Universität Ulm, 2018. http://d-nb.info/1166757064/34.

Full text
APA, Harvard, Vancouver, ISO, and other styles
42

Kyriazis, George A. "The endocytic protein Numb regulates APP metabolism and Notch signaling implications for Alzheimer's disease /." Orlando, Fla. : University of Central Florida, 2008. http://purl.fcla.edu/fcla/etd/CFE0002233.

Full text
APA, Harvard, Vancouver, ISO, and other styles
43

Kundu, Arpita [Verfasser], Donat [Gutachter] Kögel, and Jochen [Gutachter] Klein. "The role of the amyloid precursor protein (APP) in protein homeostasis and neuroprotection / Arpita Kundu ; Gutachter: Donat Kögel, Jochen Klein." Frankfurt am Main : Universitätsbibliothek Johann Christian Senckenberg, 2017. http://d-nb.info/114052576X/34.

Full text
APA, Harvard, Vancouver, ISO, and other styles
44

Bereza, Magdalena [Verfasser], Stephan [Akademischer Betreuer] Diekmann, Marcus [Akademischer Betreuer] Fändrich, and Vittorio [Akademischer Betreuer] Bellotti. "Assessment of structural diversity of ß-amyloid with genetically engineered antibody fragments / Magdalena Bereza. Gutachter: Stephan Diekmann ; Marcus Fändrich ; Vittorio Bellotti." Jena : Thüringer Universitäts- und Landesbibliothek Jena, 2013. http://d-nb.info/1033669539/34.

Full text
APA, Harvard, Vancouver, ISO, and other styles
45

Heilbronner, Götz Verfasser], and Mathias [Akademischer Betreuer] [Jucker. "Prion-Like Aspects of Beta-Amyloid Aggregation : Seeded Strain-Like Propagation of Beta-Amyloid Morphotypes and Peripheral Transmission of Cerebral Beta-Amyloidosis in APP Transgenic Mice / Götz Heilbronner ; Betreuer: Mathias Jucker." Tübingen : Universitätsbibliothek Tübingen, 2013. http://d-nb.info/1196800421/34.

Full text
APA, Harvard, Vancouver, ISO, and other styles
46

Heilbronner, Götz [Verfasser], and Mathias [Akademischer Betreuer] Jucker. "Prion-Like Aspects of Beta-Amyloid Aggregation : Seeded Strain-Like Propagation of Beta-Amyloid Morphotypes and Peripheral Transmission of Cerebral Beta-Amyloidosis in APP Transgenic Mice / Götz Heilbronner ; Betreuer: Mathias Jucker." Tübingen : Universitätsbibliothek Tübingen, 2013. http://d-nb.info/1196800421/34.

Full text
APA, Harvard, Vancouver, ISO, and other styles
47

Chang, Steffi [Verfasser], Donat [Akademischer Betreuer] Kögel, Paul G. [Akademischer Betreuer] Layer, and Ralf A. W. [Akademischer Betreuer] Galuske. "Antagonisierung von Stress-Signalwegen durch das Amyloid Precursor Protein (APP): Untersuchungen zu den molekularen Mechanismen der APP-vermittelten Neuroprotektion / Steffi Chang. Betreuer: Donat Kögel ; Paul G. Layer ; Ralf A. W. Galuske." Darmstadt : Universitäts- und Landesbibliothek Darmstadt, 2011. http://d-nb.info/1105564452/34.

Full text
APA, Harvard, Vancouver, ISO, and other styles
48

Sahlin, Charlotte. "Pathogenic Mechanisms of the Arctic Alzheimer Mutation." Doctoral thesis, Uppsala University, Department of Public Health and Caring Sciences, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7582.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, neuropathologically characterized by neurofibrillay tangles and deposition of amyloid-β (Aβ) peptides. Several mutations in the gene for amyloid precursor protein (APP) cause familial AD and affect APP processing leading to increased levels of Aβ42. However, the Arctic Alzheimer mutation (APP E693G) reduces Aβ levels. Instead, the increased tendency of Arctic Aβ peptides to form Aβ protofibrils is thought to contribute to the pathogenesis.

In this thesis, the pathogenic mechanisms of the Arctic mutation were further investigated, specifically addressing if and how the mutation affects APP processing. Evidence of a shift towards β-secretase cleavage of Arctic APP was demonstrated. Arctic APP did not appear to be an inferior substrate for α-secretase, but the availability of Arctic APP for α-secretase cleavage was reduced, with diminished levels of cell surface APP in Arctic cells. Interestingly, administration of the fatty acid docosahexaenoic acid (DHA) stimulated α-secretase cleavage and partly reversed the effects of the Arctic mutation on APP processing.

In contrast to previous findings, the Arctic mutation generated enhanced total Aβ levels suggesting increased Aβ production. Importantly, this thesis illustrates and explains why measures of both Arctic and wild type Aβ levels are highly dependent upon the Aβ assay used, with enzyme-linked immunosorbent assay (ELISA) and Western blot generating different results. It was shown that these differences were due to inefficient detection of Aβ oligomers by ELISA leading to an underestimation of total Aβ levels.

In conclusion, the Arctic APP mutation leads to AD by multiple mechanisms. It facilitates protofibril formation, but it also alters trafficking and processing of APP which leads to increased steady state levels of total Aβ, in particular at intracellular locations. Importantly, these studies highlight mechanisms, other than enhanced production of Aβ peptide monomers, which could be implicated in sporadic AD.

49

Dickey, Chad Anthony. "The influence of amyloid-beta, a major pathological marker in Alzheimer's disease, on molecular cognitive processes of APP+PS1 transgenic mice." [Tampa, Fla.] : University of South Florida, 2004. http://purl.fcla.edu/fcla/etd/SFE0000360.

Full text
APA, Harvard, Vancouver, ISO, and other styles
50

Bakir, Ilyas. "Molecular studies of the γ-secretase complex activity and selectivity towards the two substrates APP and Notch." Thesis, Mälardalen University, School of Sustainable Development of Society and Technology, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-9622.

Full text
APA, Harvard, Vancouver, ISO, and other styles
Abstract:

Alzheimer Disease (AD) is the most common neurodegenerative disorder in the world. One of the neuropathological hallmarks of AD is the senile plaques in the brain. The plaques are mainly composed of the amyloid β (Aβ) peptide. Aβ is generated from the amyloid precursor protein, APP, when it is first cleaved by the β-secretase and subsequently the γ-secretase complex. The γ-secretase complex cleaves at different sites, called γ and ε, where the γ-cleavage site generates Aβ peptides of different lengths and ε-cleavage generates the APP intracellular domain (AICD). The two major forms of Aβ is 40 and 42 amino acids long peptides, where the latter is more prone to aggregate and is the main component in senile plaques. The γ-secretase complex is composed of four proteins; Pen-2, Aph-1, nicastrin and presenilin (PS). The PS protein harbours the catalytic site of the complex, where two aspartate residues in position 257 and 385 (Presenilin 1 numbering) are situated. Most Familial AD (FAD) mutations in the PS gene cause a change in the γ-cleavage site, leading to a shift from producing Aβ40 to the longer more toxic variant Aβ42. Frequently, this often leads to impairments of the AICD production. Another substrate for the γ-secretase complex is Notch. It is important to maintain the Notch signaling since an intracellular domain (NICD) is formed after cleavage by the γ-secretase complex in the membrane (S3-site) and this domain is involved in transcription of genes important for cell fate decisions.

It has been reported that certain APP luminal juxtamembrane mutations could drastically alter Aβ secretion, however their effect on AICD production remains unknown. In this study we want to analyse wether the juxtamembrane region is important for the AICD production. To gain more insight into the luminal juxtamembrane function for γ-secretase-dependent proteolysis, we have made a juxtamembrane chimeric construct. A four-residue sequence preceding the transmembrane domain (TMD) of APP (GSNK), was replaced by its topological counterpart from the human Notch1 receptor (PPAQ). The resulting chimeric vector C99GVP-PPAQ and the wildtype counterpart were expressed in cells lacking PS1 and PS2 (BD8) together with PS1wt. We observed that the chimeric construct did not alter production of AICD when using a cell based luciferase reporter gene assay monitoring AICD production. We also introduced a PS1 variant lacking a big portion of the large hydrophilic loop, PS1∆exon10, since our group has previously observed that this region affect Aβ production143. We found that the absence of the large hydrophilic loop in PS1 gave a 2-fold decrease in AICD-GVP formation from C99GVPwt compared to PS1wt.  The activity of PS1wt and PS1Δexon10 using C99GVP-PPAQ as a substrate gave similar result as the C99GVPwt substrate, i.e. a 2-fold decrease in AICD-GVP formation when comparing PS1Δexon10 with PS1wt. From this data we therefore suggest that the four residues in the juxtramembrane domain (JMD) (GSNK) is not altering ε-cleavage of APP when changed to Notch1 counterpart, PPAQ. Furthermore, we also show that the 2-fold decrease in AICD-production by the PS1Δexon10 molecule is not changed between the two substrates C99GVPwt and C99GVP-PPAQ. This indicates that the luminal region of APP is not directly involved in the ε-site processing. If the luminal region is affecting processing in the γ-cleavage sites, remains however to be investigated.

You might also be interested in the bibliographies on the topic 'APP and amyloid fragments' for other source types:
Journal articles

To the bibliography