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Mok, Ngai Yi. "Design, synthesis and biological evaluation of new beta-secretase inhibitors." Thesis, University of Leeds, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.496529.
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Roberts, Hazel. "Alpha-synuclein expression influences the processing of the amyloid precursor protein." Thesis, University of Bath, 2016. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.707587.
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In certain neurodegenerative diseases such Dementia with Lewy Bodies (DLB), it is hypothesised that misfolded α-synuclein (α-syn) and β-amyloid both contribute to pathology. α-Syn and β-amyloid have been suggested to synergistically promote one another’s accumulation and aggregation, but the mechanisms are unknown. β-Amyloid is generated from β-/γ-secretase-mediated processing of the amyloid precursor protein (APP). This study investigated how α-syn overexpression in cells affects β-amyloid production from APP, using multiplex assays, luciferase reporter assays, and western blotting. Wildtype α-syn expression induces β-amyloid generation from APP in SH-SY5Y human neuroblastoma cells, and similar changes to APP processing occur in another neuronal cell model. Dominant-negative overexpression of α-syn mutants revealed that disrupting the N-terminal domain can increase APP amyloidogenic processing. Secretase enzymes that perform APP processing were next investigated. γ-Secretase activity, measured by a luciferase reporter, was not increased by α-syn overexpression. A higher ratio of β- to α-secretase processing was hypothesised, which led to expression and activity studies of the major β- and α-secretases, BACE1 and ADAM10 respectively. It was shown that the BACE1 protein expression is post-transcriptionally upregulated in α-syn cells, with increased APP cleavage in cells. ADAM10 protein expression is transcriptionally suppressed in wild-type α-syn cells, reducing total levels of catalytically active enzyme. However the change in ADAM10-mediated APP processing may be negligible since, critically, plasma membrane expression of ADAM10 appears to be maintained. To aid understanding of the mechanism that connects α-syn to APP processing, BACE1 expression was used in pharmacological studies of cell stress signalling. This approach revealed that in α-syn cells BACE1 lysosomal and/or proteasomal degradation may be disturbed. Additionally, BACE1 expression is induced by translational de-repression mediated by eIF2α ser-51 phosphorylation, which was increased in α-syn cells. Although preliminary, the data suggests a role for oxidative stress mediating the increased BACE1 expression in wild-type α-syn cells.
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Semighini, Evandro Pizeta. "Planejamento racional de inibidores da beta-secretase em mal de Alzheimer." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/60/60136/tde-06092013-102421/.
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O Mal de Alzheimer é o maior causador de demência em idosos: acomete 10% da população mundial com idade em torno dos 65 anos e atinge cerca de 50% dos indivíduos com mais de 85 anos. A progressão dos sintomas da doença está associada a modificações estruturais nas sinapses colinérgicas em determinadas regiões cerebrais. A maior característica fisiopatológica do AD é a deposição de placas neuríticas extracelulares em áreas cerebrais relacionadas à memória, placas constituídas pelo peptídeo ?-amiloide 40/42, que é formado pela clivagem da Proteína Precursora Amiloide, durante seu metabolismo pela via amiloidogênica, que começa com a enzima ?-secretase. O objetivo do trabalho foi o planejamento e avaliação de novos inibidores de ?-secretase. Para isso, foram utilizadas diferentes técnicas de modelagem molecular e planejamento de moléculas, tendo como base os inibidores da ?-secretase descritos na literatura cujas estruturas estão depositadas no PDB. Posteriormente, foi realizada a avaliação in vitro da atividade inibitória de algumas destas moléculas, onde observou-se que três são capazes de satisfatoriamente inibir a atividade da ?-secretase na concentração de 1 µM.The Alzheimer\'s disease is the major cause of elderly dementia: it affects 10% of global population with 65 years old and about 50% of individuals with 85 years old or more. The evolution of the disease symptoms is associated with structural changes in cholinergic synapses at certain brain regions. The major pathophysiological feature of AD is the deposition of extracellular neuritic plaques in areas of the brain related to memory. The ?-amyloid peptide 40/42 constitutes the plaques. It\'s formed by cleavage of the amyloid precursor protein during its metabolism by the amyloidogenic pathway, which starts with the ?-secretase enzyme. The goal of this project was the planning and evaluation of new ?-secretase inhibitors activity. For this, we used different molecular modeling and drug design techniques, based on the ?-secretase inhibitors described in the literature, whose structures are deposited in the PDB, with subsequent in vitro evaluation of this molecules activity. The in vitro assays showed three molecules able to inhibit ?-secretase at 1 µM.
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Liu, Wei Wei. "An investigation of beta-secretase activity and regulation in Alzheimer's disease." Thesis, Queen's University Belfast, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486241.
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Alzheimer's disease (AD) is the most common cause of dementia, characterized by the • presence of extracellular amyloid plaques and intracellular tangles in the brain. The principal component of amyloid plaques is the amyloid 13 (A13) peptide, cleaved from amyloid precursor protein (APP) by 13-secretase and y-secretase. Two proteases with 13-secretase activity have been identified: 13-site APP-cleaving enzymes 1 and 2 (BACE1 and BACE2). Previous post. mortem studies have revealed an increase of 13-secretase activity in brain tissue of individuals with sporadic AD. This study aimed to investigate whether platelet 13-secretase activity was elevated in individuals with AD or mild cognitive impairment (MCI). An assay of 13-secretase activity was established and characterised (chapter 3) using small peptide f1uorogenic sUbstrates, based on the region of APP which 13-secretase normally cleaves. This assay was then applied to a large group of platelet samples from individuals with AD. or MCI, or from controls (total 331 samples) (chapter 4). This· work revealed that although there was considerable variation in platelet 13-secretase activity between individuals. the group of people with AD or MCI had a statistically significant higher activity than did age-matched controls. We then investigated a range of factors that could potentially contribute to the inter-individual variation in 13-secretase activity. Platelet 13-secretase activity did not correlate with BACE1 protein level in a subset of samples (n = 28). indicating that it might be regulated by factors other than BACE1 expression. Interestingly, a significant correlation between platelet membrane 13-secretase activity and platelet membrane cholesterol level was identified. This led tQ our investigation of the relationship between membrane. cholesterol level and membrane 13-secretase activity in SH-SY5Y cells (chapter 5). This work revealed a reciprocal and biphasic relationship between membrane cholesterol level and membrane 13-secretase activity. a relationship that may also be present in human platelets
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Cordy, Joanna Margaret. "The involvement of lipid rafts in the regulation of beta-secretase activity." Thesis, University of Leeds, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411357.
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Chiocco, Matthew J. "Beta-secretase transgenic mice effects of BACE1 and BACE2 on Alzheimer's disease pathogenesis /." Connect to text online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1111597750.
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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.
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Wiley, Jesse Carey. "Familial Alzheimer's disease mutations decrease gamma-secretase processing of beta amyloid precurson [sic] protein /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/4985.
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MuÑoz, Gimenez Noeli. "Identification et Caractérisation d'une Enzyme de type beta-Secretase Impliquée dans la Maturation Protéolytique du Précurseur du Peptide beta-Amyloide." Paris 6, 1999. http://www.theses.fr/1999PA066688.
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Matera, Riccardo <1977>. "Design and synthesis of novel non peptidomimtic beta-secretase inhibitors in the treatment of Alzheimer's disease." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2009. http://amsdottorato.unibo.it/1711/.
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The aspartic protease BACE1 (β-amyloid precursor protein cleaving enzyme, β-secretase) is recognized as one of the most promising targets in the treatment of Alzheimer's disease (AD). The accumulation of β-amyloid peptide (Aβ) in the brain is a major factor in the pathogenesis of AD. Aβ is formed by initial cleavage of β-amyloid precursor protein (APP) by β-secretase, therefore BACE1 inhibition represents one of the therapeutic approaches to control progression of AD, by preventing the abnormal generation of Aβ. For this reason, in the last decade, many research efforts have focused at the identification of new BACE1 inhibitors as drug candidates. Generally, BACE1 inhibitors are grouped into two families: substrate-based inhibitors, designed as peptidomimetic inhibitors, and non-peptidomimetic ones. The research on non-peptidomimetic small molecules BACE1 inhibitors remains the most interesting approach, since these compounds hold an improved bioavailability after systemic administration, due to a good blood-brain barrier permeability in comparison to peptidomimetic inhibitors.
Very recently, our research group discovered a new promising lead compound for the treatment of AD, named lipocrine, a hybrid derivative between lipoic acid and the AChE inhibitor (AChEI) tacrine, characterized by a tetrahydroacridinic moiety. Lipocrine is one of the first compounds able to inhibit the catalytic activity of AChE and AChE-induced amyloid-β aggregation and to protect against reactive oxygen species. Due to this interesting profile, lipocrine was also evaluated for BACE1 inhibitory activity, resulting in a potent lead compound for BACE1 inhibition. Starting from this interesting profile, a series of tetrahydroacridine analogues were synthesised varying the chain length between the two fragments. Moreover, following the approach of combining in a single molecule two different pharmacophores, we designed and synthesised different compounds bearing the moieties of known AChEIs (rivastigmine and caproctamine) coupled with lipoic acid, since it was shown that dithiolane group is an important structural feature of lipocrine for the optimal inhibition of BACE1. All the tetrahydroacridines, rivastigmine and caproctamine-based compounds, were evaluated for BACE1 inhibitory activity in a FRET (fluorescence resonance energy transfer) enzymatic assay (test A). With the aim to enhancing the biological activity of the lead compound, we applied the molecular simplification approach to design and synthesize novel heterocyclic compounds related to lipocrine, in which the tetrahydroacridine moiety was replaced by 4-amino-quinoline or 4-amino-quinazoline rings. All the synthesized compounds were also evaluated in a modified FRET enzymatic assay (test B), changing the fluorescent substrate for enzymatic BACE1 cleavage. This test method guided deep structure-activity relationships for BACE1 inhibition on the most promising quinazoline-based derivatives. By varying the substituent on the 2-position of the quinazoline ring and by replacing the lipoic acid residue in lateral chain with different moieties (i.e. trans-ferulic acid, a known antioxidant molecule), a series of quinazoline derivatives were obtained. In order to confirm inhibitory activity of the most active compounds, they were evaluated with a third FRET assay (test C) which, surprisingly, did not confirm the previous good activity profiles. An evaluation study of kinetic parameters of the three assays revealed that method C is endowed with the best specificity and enzymatic efficiency. Biological evaluation of the modified 2,4-diamino-quinazoline derivatives measured through the method C, allow to obtain a new lead compound bearing the trans-ferulic acid residue coupled to 2,4-diamino-quinazoline core endowed with a good BACE1 inhibitory activity (IC50 = 0.8 mM). We reported on the variability of the results in the three different FRET assays that are known to have some disadvantages in term of interference rates that are strongly dependent on compound properties. The observed results variability could be also ascribed to different enzyme origin, varied substrate and different fluorescent groups. The inhibitors should be tested on a parallel screening in order to have a more reliable data prior to be tested into cellular assay. With this aim, preliminary cellular BACE1 inhibition assay carried out on lipocrine confirmed a good cellular activity profile (EC50 = 3.7 mM) strengthening the idea to find a small molecule non-peptidomimetic compound as BACE1 inhibitor. In conclusion, the present study allowed to identify a new lead compound endowed with BACE1 inhibitory activity in submicromolar range. Further lead optimization to the obtained derivative is needed in order to obtain a more potent and a selective BACE1 inhibitor based on 2,4-diamino-quinazoline scaffold.
A side project related to the synthesis of novel enzymatic inhibitors of BACE1 in order to explore the pseudopeptidic transition-state isosteres chemistry was carried out during research stage at Università de Montrèal (Canada) in Hanessian's group. The aim of this work has been the synthesis of the δ-aminocyclohexane carboxylic acid motif with stereochemically defined substitution to incorporating such a constrained core in potential BACE1 inhibitors. This fragment, endowed with reduced peptidic character, is not known in the context of peptidomimetic design. In particular, we envisioned an alternative route based on an organocatalytic asymmetric conjugate addition of nitroalkanes to cyclohexenone in presence of D-proline and trans-2,5-dimethylpiperazine. The enantioenriched obtained 3-(α-nitroalkyl)-cyclohexanones were further functionalized to give the corresponding δ-nitroalkyl cyclohexane carboxylic acids. These intermediates were elaborated to the target structures 3-(α-aminoalkyl)-1-cyclohexane carboxylic acids in a new readily accessible way.
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Todd, S. A. "Beta-secretase activity in huaman blood platelets in patients and relationships to polymorphisms in BACE in Alzheimer's disease and control subjects." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492482.
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This study aimed to investigate whether there are differences in the ~-secretase activity in the platelets of Alzheimer's disease (AD) subjects and cognitively normal control subjects and to determine whether the concentration of cholesterol influences this activity. A further aim was to study whether the apolipoprotein (ApoE) £4 allele or polymorphisms in the ~-site amyloid precursor protein cleaving enzyme (BACE1) gene are associated with AD or with alterations in the ~-secretase activity in platelets. METHODS: Subjects with a diagnosis of AD (NINCDS - ADRDA) were recruited from a regional Memory Clinic. Control subjects with no evidence of cognitive impairment were also recruited. Blood samples were drawn for assay of ~-secretase activity and genetic analyses. Statistical analysis was performed using SPSS for Windows version 14, GraphPad version 4, and HaploView version 4. RESULTS: 399 SUbjects were recruited; 201 with probable AD and 198 controls. Mean platelet membrane ~-secretase activity was significantly higher in the AD group, compared to the control group. Age and serum cholesterol concentration were significantly higher in the AD group, but did not correlate with the platelet membrane ~-secretase activity. Platelet membrane cholesterol concentration was significantly lower in the AD group and was significantly positively IlI I, I I' I~ I I! ---------------------- correlated with the platelet membrane ~-secretase activity. ApoE £4 was strongly associated with AD but did not correlate with the platelet membrane ~-secretase activity. Variation in the BACE1 gene was not associated with AD and did not correlate with the platelet membrane ~-secretase activity. CONCLUSIONS: Platelet membrane ~-secretase activity is elevated in AD and is correlated with the platelet membrane cholesterol concentration. Common variants in the BACE1 gene do not influence the genetic susceptibility for AD in the NI population.
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Py, Nathalie. "Métalloprotéases matricielles et maladie d'Alzheimer : étude du rôle de MT1-MMP dans le métabolisme de l'APP/Aß." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5073.
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La maladie d'Alzheimer (MA) est la maladie neurodégénérative la plus répandue à travers le monde et reste actuellement incurable. Le peptide beta amyloïde (Abeta), composant principal des plaques séniles retrouvées dans le cerveau des patients, joue un rôle majeur dans le développement de la MA, d'où l'importance de contrôler sa production et/ou son élimination. Dans cette optique, nous travaillons sur des molécules nommées métalloprotéases matricielles (MMPs). Bien qu'ayant été impliquées à la fois dans de nombreux processus physiologiques et pathologiques dans système nerveux, leur rôle dans la MA reste encore relativement inexplorée. Nous avons utilisé comme modèle d'étude des souris qui développent les symptômes de la MA (déclin cognitif, mort des neurones). Nous montrons que deux MMPs, MMP-2 et MT1-MMP, augmentent leurs niveaux d'expression avec le vieillissement de l'animal et donc avec l'aggravation de la pathologie. Ceci a lieu dans l'hippocampe, une région du cerveau qui est particulièrement sensible car elle est impliquée dans l'apprentissage et la mémoire. Par la suite nous avons utilisé des cellules HEKswe qui produisent beaucoup d'Abeta et miment d'une certaine manière ce qui se passe dans le cerveau de la souris, afin de mieux appréhender la signification des augmentations de ces MMPs. Nous montrons que la surexpression de MT1-MMP dans ces cellules favorise la formation d'Abeta, alors que MMP-2 l'empêche. Ces résultats montrent pour la première fois une dualité fonctionnelle au sein de la famille des MMPs, et plus important, révèlent une nouvelle molécule amyloïdogénique (MT1-MMP) qui pourrait devenir à terme une cible thérapeutiqueWe investigate the role of matrix metalloproteinases in the metabolism of beta amyloid peptide (Abeta) and its amyloid precursor protein (APP) in Alzheimer's disease (AD). Our results in the 5xFAD mouse model of AD indicate a cell-type and age-dependent upregulation of MMP-2 -and MT1-MMP active forms. This is concomitant with the increase of toxic forms of Abeta, but also of cytotoxic C99, a membrane fragment of APP generated by beta-secretase and that gives rise to Abeta after gamma-secretase cleavage. We show in HEK cells overproducing Abeta that while MT1-MMP interacts with APP and boosts C99 and Abeta production, MMP-2 does not interact with APP and degrades Abeta. These results uncover a MMP-specific regulatory crosstalk with amyloid and also MT1-MMP as a new pro-amyloidogenic proteinase. We want now to gain further insight into the mechanisms that support MT1-MMP effects, namely the possible modulation by MT1-MMP of beta- and gamma-secretase activities and/or APP trafficking
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Barat, Samarpita [Verfasser], and Ruben [Akademischer Betreuer] Plentz. "Gamma-secretase inhibitor IX (GSI) impairs concomitant activation of Notch and wnt-beta-catenin pathways in CD44+ gastric cancer / Samarpita Barat ; Betreuer: Ruben Plentz." Tübingen : Universitätsbibliothek Tübingen, 2016. http://d-nb.info/1199615560/34.
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Capell, Anja. "Funktionelle Charakterisierung von BACE, einer für die Alzheimer Krankheit relevanten Protease." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2005. http://dx.doi.org/10.18452/15321.
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Die Alzheimer Krankheit ist die häufigste Altersdemenz. Ein spezifisches pathologisches Merkmal der Alzheimer Krankheit ist die Amyloid-Ablagerung im Gehirn. Die Hauptkomponente der so genannten Amyloid-Plaques ist das Amyloid beta-Peptid (A-beta). A-beta entsteht durch sequenzielle proteolytische Spaltung aus einem membrangebundenen Vorläuferprotein, dem beta-APP (betaamyloid precursor protein). Die kürzlich identifizierte beta-Sekretase (BACE, beta-site APPcleaving enzyme) generiert den Schnitt am N-Terminus von A-beta. Es entsteht ein C-terminales, membrangebundenes beta-APP-Fragment, das beta-APP-CTF. Beta-APP-CTF ist das direkte Substrat für die gamma-Sekretase, die innerhalb der Membrandomäne schneidet, wodurch A-beta freigesetzt wird. In der vorliegenden Arbeit kann erstmalig gezeigt werden, dass BACE auf dem sekretorischen Transportweg aus dem Endoplasmatischen Retikulum (ER), über den Golgi-Apparat zur Zelloberfläche transportiert wird. Auf dem Transport wird BACE durch N-Glycosylierung und Propeptidabspaltung posttranslational modifiziert. BACE wird im ER N-glycosyliert und die mannosereichen Zucker werden auf dem Transport durch den Golgi-Apparat in Endoglycosidase H resistente Zucker des komplexen Typs modifiziert. Die Propeptidabspaltung, durch Furin oder furinähnliche Propeptidkonvertasen, findet unmittelbar vor dem Aufbau der komplexen Zucker statt. Ferner konnte gezeigt werden, dass der Transport von BACE die A-beta-Entstehung limitieren kann. In polarisierten Madin-Darby canine kidney (MDCK) Zellen wird BACE überwiegend zur apikalen Plasmamembran transportiert und damit entgegengesetzt zu seinem Substrat beta-APP. Der gegensätzliche Transport von BACE und beta-APP begrenzt die A-beta Entstehung. Wird der apikale Transport von beta-APP durch Deletion seines basolateralen Sortierungssignals erhöht, entsteht vermehrt A-beta. Der differenzielle Transport von BACE und beta-APP könnte ein Hinweis darauf sein, dass beta-APP nicht das physiologische Substrat von BACE ist.Alzheimer`s disease is the most common cause of progressive cognitive decline in the aged population. Pathologically Alzheimer`s disease is characterized by the invariant accumulation of senile plaques. Senile plaques are predominantly composed of the amyloid beta-peptide (A-beta), which is derived from the membrane bound beta-amyloid precursor protein (beta-APP) by sequential proteolytic cleavage. The recently identified beta-secretase (BACE) is responsible for the cleavage at the N-terminus of the A-beta domain. This cleavage generates membrane-bound beta-APP-Cterminal fragments (beta-APP-CTF) which are the immediate precursor for gamma-secretase cleavage and therefore for liberation of A-beta. The present work shows that BACE moves along the secretory pathway, while it undergoes post-translational modifications, which can be monitored by a significant increase in the molecular mass and cleavage of its pro-peptide. BACE becomes N-glycosylated within the ER and the increase in molecular mass is caused by complex N-glycosylation. The mature form of BACE is resistant to endoglycosidase H treatment; this indicates that BACE traffics through the Golgi. Furthermore the mature form of BACE does not contain the pro-peptide anymore. Pro-BACE is predominantly located within the endoplasmic reticulum. Pro-peptide cleavage occurs immediately before full maturation by furin or a furin-like proprotein convertase. Moreover traffic of BACE can limit A-beta generation. In the well established model system of polarized Madin-Darby canine kidney (MDCK) cells, the majority of BACE is sorted to the apical domain. Interestingly it has been shown previously that the substrate of BACE, beta-APP is transported to the basolateral surface of MCDK cells. Therefore, substantial amounts of BACE are targeted away from beta-APP to a non-amyloidogenic compartment, a cellular mechanism that limits A-beta generation. Upon deletion of the basolateral sorting signal of beta-APP, apically missorted beta-APP is processed by BACE. The differential targeting of BACE and its substrate beta-APP suggest that beta-APP might not be the major physiological substrate of BACE.
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Kalvodova, Lucie. "Reconstituting APP and BACE in proteoliposomes to characterize lipid requirements for β-secretase activity." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2006. http://nbn-resolving.de/urn:nbn:de:swb:14-1158242647401-41976.
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Proteolytic processing of the amyloid precursor protein (APP) may lead to the formation of the Abeta peptide, the major constituent of amyloid plaques in Alzheimer`s disease. The full-length APP is a substrate for at least 2 different (alpha and beta) proteases ("secretases"). The beta-secretase, BACE, cleaves APP in the first step of processing leading to the formation of the neurotoxic Abeta. BACE competes for APP with alpha-secretase, which cleaves APP within its Abeta sequence, thus precluding Abeta formation. It is thus important to understand how is the access of the alpha- and beta-secretase to APP regulated and how are the individual activities of these secretases modulated. Both these regulatory mechanisms, access to substrate and direct activity modulation, can be determined by the lipid composition of the membrane. Integral membrane proteins (like APP and BACE), can be viewed as solutes in a two-dimensional liquid membrane, and as such their state, and biological activity, critically depend on the physico-chemical character (fluidity, curvature, surface charge distribution, lateral domain heterogeneity etc.) of the lipid bilayer. These collective membrane properties will influence the activity of embedded membrane proteins. In addition, activity regulation may involve a direct interaction with a specific lipid (cofactor or co-structure function). Interactions of membrane proteins are furthermore affected by lateral domain organization of the membrane. Previous results had suggested that the regulation of the activity of the alpha- and beta-secretases and of their access to APP is lipid dependent, and involves lipid rafts. Using the baculovirus expression system, we have purified recombinant human full-length APP and BACE to homogeneity, and reconstituted them in large (~100nm, LUVs) and giant (10-150microm, GUVs) unilamellar vesicles. Using a soluble peptide substrate mimicking the beta-cleavage site of APP, we have examined the involvement of individual lipid species in modulating BACE activity in LUVs of various lipid compositions. We have identified 3 groups of lipids that stimulate proteolytic activity of BACE: 1.cerebrosides, 2.anionic glycerophospholipids, 3. cholesterol. Furthermore, we have co-reconstituted APP and BACE together in LUVs and demonstrated that BACE cleaves APP at the correct site, generating the beta-cleaved ectodomain identical to that from cells. We have developed an assay to quantitatively follow the beta-cleavage in proteoliposomes, and we have shown that the rate of cleavage in total brain lipid proteoliposomes is higher than in phosphatidylcholine vesicles. We have also studied partitioning of APP and BACE in GUVs between liquid ordered (lo) and liquid disordered (ld) phases. In this system, significant part of the BACE pool (about 20%) partitions into the lo phase, and its partitioning into lo phase can be further enhanced by cross-linking of membrane components. Only negligible fraction of APP can be found in the lo phase. We continue to study the behavior of co-reconstituted APP and BACE in GUVs The work presented in this thesis has yielded some interesting results and raised further questions. One of the important assignments of this project will in the next stage be the characterization of the impact of membrane domain organization on the beta-cleavage. Different domain arrangements that can be hypothesized in cell membranes can be modeled by varying the degree of phase fragmentation in proteoliposomes comprising reconstituted APP and BACE.
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Kumar, Arun Babu. "Design, Synthesis and Evaluation of Novel Diazirine Photolabels with Improved Ambient Light Stability and Fluorous-Based Enrichment Capacity." Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4112.
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Photoaffinity labeling is a quintessential technique in studying and analyzing the interaction between a ligand and receptor. Diazirines are one of the important photo-labile moieties used in photoaffinity labeling due to their superior photo labeling characteristics. Herein, we report the investigations we conducted with diazirine photolabels on (a) photochemical aspects leading to enhancement of their ambient light stability and (b) equipping them with fluorous tags to enable fluorous enrichment of labeled proteins. Furthermore, we report a pilot study to develop BACE-1 inhibitors, which have potential to be developed into photoaffinity probes.
3-Trifluoromethyl-3-phenyldiazirine offers good selectivity and protection against pseudolabeling but due to its photo lability, it undergoes decomposition even under ambient light. Thus the laboratory handling, including synthesis, of 3-trifluoromethyl-3-phenyldiazirine is cumbersome and restricted under constant darkness. Herein, we have designed, synthesized and evaluated two photolabels with enhanced stability to ambient light conditions in addition to the good selectivity and protection against pseudolabeling as offered by 3-trifluoromethyl-3-phenyldiazirine. It was also found that the aqueous solubility, a vital physical property for a photolabel, was also improved in the modified ambient light stable photolabels.
Fluorous tags have found wide use in synthetic applications; herein we explore the possibility of its application in photoaffinity studies. We designed, synthesized and conducted photoactivation studies on two fluorous diazirine photolabels. The photoactivation studies unraveled an unanticipated photoreaction when the fluorous tag
was directly connected to the diazirine ring, yielding a fluorous alkene. The more practical photolabel of the two was chosen as the target specific photoaffinity labeling moiety for fluorous proteomics. Upon conducting photolabeling experiments under various conditions, we found that the strong hydrophobic character of the fluorous tag renders the photoaffinity label insoluble in aqueous solutions and significantly alters the binding mode and affinity of the photoaffinity label to its target receptor.
A library of 1,3-disubstituted 2-propanols was combinatorially prepared and tested as small molecule inhibitors of β-secretase (BACE-1). The initial screening of the 1,3-disubstituted 2-propanol library revealed a few low micromolar inhibitors for BACE-1. The compound that showed the best activity was chosen for further SAR studies, which resulted in a potent BACE-1 inhibitor with nanomolar inhibition. Investigation on the selectivity of these compounds for BACE-1 inhibition over cathepsin D revealed that these compound series possess very high selectivity. Furthermore, the physicochemical properties study showed that these compounds possessed the calculated parameters advantageous to cross the blood-brain barrier (BBB).
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Linning, Philipp, Ute Haussmann, Isaak Beyer, Sebastian Weidlich, Heinke Schieb, Jens Wiltfang, Hans-Wolfgang Klafki, and Hans-Joachim Knölker. "Optimisation of BACE1 inhibition of tripartite structures by modification of membrane anchors, spacers and pharmacophores – development of potential agents for the treatment of Alzheimer's disease." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-138993.
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Systematic variation of membrane anchor, spacer and pharmacophore building blocks leads to an optimisation of the inhibitory effect of tripartite structures towards BACE1-induced cleavage of the amyloid precursor protein (APP)Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Linning, Philipp, Ute Haussmann, Isaak Beyer, Sebastian Weidlich, Heinke Schieb, Jens Wiltfang, Hans-Wolfgang Klafki, and Hans-Joachim Knölker. "Optimisation of BACE1 inhibition of tripartite structures by modification of membrane anchors, spacers and pharmacophores – development of potential agents for the treatment of Alzheimer's disease." Royal Society of Chemistry, 2012. https://tud.qucosa.de/id/qucosa%3A27800.
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Systematic variation of membrane anchor, spacer and pharmacophore building blocks leads to an optimisation of the inhibitory effect of tripartite structures towards BACE1-induced cleavage of the amyloid precursor protein (APP).Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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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.
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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’APPA 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
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Kalvodová, Lucie [Verfasser]. "Reconstituting APP and BACE in proteoliposomes to characterize lipid requirements for ß-secretase [Beta-secretase] activity / by Lucie Kalvodová." 2006. http://d-nb.info/982371381/34.
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Lin, Po-Han, and 林柏翰. "Preparation of spiro nucleoside analogs as inhibitors of beta-secretase 1." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/8sb5x4.
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Umbreen, Sumaira [Verfasser]. "Synthesis and biological evaluation of β-secretase [beta-secretase] inhibitors, proteasome inhibitors and Losartan active metabolites / vorgelegt von Sumaira Umbreen." 2007. http://d-nb.info/984602291/34.
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Pereira, Rita Alexandra Gonçalves. "Síntese de um potencial inibidor da B-secretase e sua interação com o enzima." Master's thesis, 2012. http://hdl.handle.net/10400.6/2868.
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A doença de Alzheimer é a doença neurodegenerativa mais comum durante o envelhecimento, sendo uma das maiores preocupações de saúde pública e uma prioridade para investigação, uma vez que, os tratamentos aprovados apenas atenuam os sintomas da doença, sendo incapazes de parar a progressão da doença. Deste modo, existe um grande interesse no desenvolvimento de novas estratégias terapêuticas que visem os mecanismos moleculares que estão na origem da doença, de forma a atrasar ou mesmo parar a progressão da doença. De acordo com a hipótese dominante no campo de investigação da doença de Alzheimer, a hipótese da cascata amilóide, preconiza que a acumulação de elevados níveis do péptido β-amilóide no cérebro é responsável por desencadear uma sequência de eventos que acabam por conduzir à morte neuronal e consequentemente à demência, por isso, atualmente a maioria dos ensaios clínicos são desenhados tendo em como alvo terapêutico o péptido β-amilóide, ou seja, um dos maiores alvos terapêuticos nesta área é a β-secretase envolvida no processamento da proteína precursora amilóide e consequente formação do péptido β-amilóide. Este trabalho teve como objetivo sintetizar compostos derivados de açúcares com potencial aplicação terapêutica na doença de Alzheimer, mais precisamente, como potenciais inibidores da β-secretase, uma vez que é um alvo bastante interessante por poder ser inibida por compostos de baixa massa molecular. No que diz respeito ao primeiro objetivo, foi sintetizada a lactona 2,3,5,6-tetra-O-benzil-D-glucono-1,4-lactona (7), precursora da molécula-alvo, com um rendimento de 81%. Seguidamente sintetizou-se o produto N-benzil-2,3,5,6-tetra-O-benzil-D-gluconamida (8) com 55 % de rendimento. Outra das moléculas-alvo a sintetizar era o ácido 3-(2,3,5,6-tetra-O-benzil-D-gluconamido) propano-1-sulfónico (10b), no entanto pela caracterização espetroscópica de Ressonância Magnética Nuclear pode-se constatar que não se conseguiu obter este produto pretendido. A elucidação da sua estrutura requer a utilização de outros métodos complementares, nomeadamente a espetroscopia de massa. Os estudos computacionais de Docking para avaliar a interação dos compostos pretendidos com a β-secretase de modo a confirmar se tais produtos poderiam ser potenciais inibidores deste enzima, estão a ser realizados com os produtos N-benzil-2,3,5,6-tetra-O-benzil-D-gluconamida e com o ácido 3-(2,3,5,6-tetra-O-benzil-D-gluconamido) propano-1-sulfónico. Porém estes estudos de Docking ainda estão a decorrer, não tendo ainda resultados para apresentar nesta dissertação.Alzheimer’s disease is the most common neurodegenerative disease in ageing. This disease is a major public concern and a priority for research, since the only approved treatments alleviate the symptoms of the disease, being unable to stop the progression of the disease. Thus, there is great interest in developing new therapeutic strategies that target the molecular mechanisms that cause the disease in order to delay or even stop disease progression. According to the dominant hypothesis in research of Alzheimer's disease, the amyloid cascade hypothesis, suggests that the accumulation of high levels of β-amyloid peptide in the brain is responsible for triggering a sequence of events that ultimately lead to neuronal death and consequently dementia. Therefore, currently the majority of clinical trials are designed with β-amyloid peptide as therapeutic target. Another therapeutic target is the β-secretase, an enzyme involved in processing amyloid precursor protein and subsequent formation of β-amyloid peptide. This study aims to synthesize compounds derived from sugars with potential therapeutic application in Alzheimer's disease, more specifically as potential inhibitors of β-secretase, that can be inhibited by compounds of low molecular weight. For the purpose the lactone 2,3,5,6-tetra-O-benzyl-D-glucono-1,4-lactone (7) was chosen as starting material and its synthesis investigated and successfully conducted to give this target molecule in 81% yield. Its transformation into amides was the next step and Nbenzyl-2,3,5,6-tetra-O-benzyl-D-gluconamide (8) was obtained in fairly good yield (55% yield). Preliminary experiments towards the synthesis of 3-(2,3,5,6-tetra-O-benzyl-D-gluconamide)- 1-propane sulfonic acid were carried out, however characterization by nuclear magnetic resonance of the product formed were not conclusive to elucidate the structure of the compound obtained and additional methods, namely mass spectrometry are required to assign the structure of the final product. The computational studies to evaluate the interaction of the desired compounds with β-secretase are being carried out with N-benzyl-2,3,5,6-tetra-Obenzyl-D-gluconamide and 3-(2,3,5,6-tetra-O-benzyl-D-gluconamide) sulfonic acid. The docking studies are still ongoing and we expect these results will give a contribution to innovation in Alzheimer’s therapy.
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Jeon, Amy Hye Won. "Comparative Interactome Investigation of γ-secretase Complex in Alzheimer’s Disease." Thesis, 2012. http://hdl.handle.net/1807/43389.
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γ-Secretase plays a pivotal role in the production of neurotoxic amyloid β-peptide (Aβ), the principal component of amyloid plaques present in Alzheimer’s disease. It consists of a core complex of presenilin (PS), nicastrin, anterior pharynx-defective 1 (Aph-1), and presenilin enhancer 2 (Pen-2) proteins. PS harbors the catalytic aspartates required for regulated intramembrane proteolysis and the paralogs (PS1 and PS2) contribute to the assembly of distinct subpopulations of γ-secretases that may fulfill distinct roles. To characterize the molecular environments of distinct γ-secretases complexes in-depth quantitative comparisons were performed on 1) wild-type PS1 and its derivative carrying point mutations known to cause heritable early-onset AD in mice, and 2) PS1- or PS2-containing γ-secretase complexes equipped with N-terminal tandem-affinity purification (TAP) tags on PS paralogs in HEK293 cells. Isobaric labeling of co-purifying peptides for quantitative mass spectrometry revealed that γ-secretase complexes interact with other protein networks, including the cellular catenin-cadherin network, the molecular machinery that targets and fuses synaptic vesicles to cellular membranes, and the H+-transporting lysosomal ATPase macro-complex. The study revealed mature γ-secretase complexes containing PS1 or mutant PS1 to be indistinguishable in their protein composition, confirmed several previously proposed γ-secretase interactors, identified many novel interactors and uncovered a subset of proteins which can engage in robust interactions with γ-secretase complexes in individual cell types but may escape detection when whole brains are used as biological source materials. Interestingly, signal peptide peptidase (SPP), a Type II TM cleaving aspartyl protease, was pre-dominantly found to co-purify with PS2-containing γ-secretase complexes and could be shown not to influence their maturation but to affect cleavage or release of cellular Aβ. A model emerged from this work that suggests PS1 and PS2 paralogs may divide up the task of handling a broad range of membrane stubs at least in part by associating with different molecular environments.
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Folk, Drew Steven. "Development of a beta-Secretase Activated Prochelator and FRET Probe to Mediate Copper Toxicity in Alzheimer's Disease." Diss., 2012. http://hdl.handle.net/10161/5825.
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Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects over 5 million people in the United States alone. This number is predicted to triple to by the year 2050 due to both increasing life expectancies and the absence of disease-attenuating drugs. The etiology of AD remains unclear, and although there are multiple theories implicating everything from oxidative stress to protein misfolding, misregulated metal ions appear as a common thread in disease pathology.
Chelation therapy has shown some effectiveness in clinical trials, but to date, there are no FDA-approved metal chelators for the treatment of AD. One of the biggest problems with general chelators is their inability to differentiate between the metal ions involved in disease progression verses those involved in normal metabolic function. To address this problem, we have developed a prochelator approach whereby the prochelator (SWH) does not bind metals with significant biological affinity. However, once activated to the chelator (CP) via enzymatic hydrolysis, the molecule is able to bind copper and reduce its toxicity both in vitro and in a cellular model of Alzheimer's Disease.
Central to this strategy is the site-specificity provided by enzymatic activation of the prochelator. In our system, SWH to CP conversion is mediated by beta-secretase, an enzyme involved in A-beta generation. However, in order to render SWH capable of hydrolysis in cells, we modified the prochelator to contain a dihydrocholesterol membrane anchor attached via a polyethylene glycol linker. From this construct, we created beta-MAP, which is an SWH-based FRET probe to demonstrate beta-secretase-mediated conversion of SWH to CP. beta-MAP was also used to confirm the efficacy of a known beta-secretase inhibitor without the need to for mutated cells lines or expensive antibodies. beta;-MAP and the associated microscopy method represent a significant advancement to the currently available ELISA assays for beta-secretase activity.
While activation of the prochelator by an enzyme in cells is encouraging, non-specific hydrolysis of the peptide prevents significant accumulation of the chelator on the cell membrane. Furthermore, attachment of the polyethylene glycol and sterol units induce cell toxicity not seen with the native CP peptide. These drawbacks prevent the current prochelator from effectively protecting cells from AD conditions. Structural modifications to overcome these problems, including implementation of a new peptide sequence are planned for future experiments.
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Nogueira, Ana Sofia Soares. "Development of plasma Aβ assays for disease modifying approaches in Alzheimer’s disease." Master's thesis, 2013. http://hdl.handle.net/10316/24749.
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Dissertação de mestrado em Biologia Celular e Molecular com especialização em Neurobiologia, apresentada ao Departamento Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de Coimbra.A doença de Alzheimer (DA) é uma doença neuro degenerativa progressiva sendo a maior causa de demência no mundo. As caracteristicas neuropatológicos desta doença são a acumulação extracelular de péptidos de beta-amilóide (Aβ) e a agregação intracelular de tau hiperfosforilada. Os péptidos Aβ são formados na via amiloidogénica, através do processamento proteolítico da proteína precursora do péptido Aβ (APP) pelas enzimas β- e γ-secretase. Tem sido sugerido que a formação destes péptidos é o evento que desencadeia o desenvolvimento de AD. Hoje em dia, apenas tratamentos sintomáticos se encontram ao dispor destes pacientes. A procura de fármacos com potencial de alterar a progressão da doença é uma área activa de investigação na indústria farmacêutica, encontrando-se alguns compostos em avaliação, em ensaios clínicos. Vários alvos envolvidos na produção e eliminação do péptido Aβ têm sido estudados como potenciais alvos terapêuticos. Inibidores de β-secretase diminuem a produção das formas do péptido Aβ mais longas e com maior potencial de auto-agregação, tais como o péptido Aβ1-42. Biomarcadores permitem não só prever e observar a progressão da DA, mas também monotorizar a eficácia de compostos que permitam alterar a progressão da doença. Biomarcadores actualmente disponíveis para o diagnóstico e avaliação da eficácia de tratamentos incluem marcadores bioquímicos no líquido cefalorraquidiano (LCR) e imagiologia cerebral. No entanto, ambos apresentam limitações: a recolha de LCR é um procedimento invasivo e com possíveis efeitos secundários para os pacientes e imagiologia cerebral é uma técnica com custos elevados. Recentemente, tem sido sugerido que a medição do péptido Aβ em plasma é uma ferramenta de baixo custo e não invasiva para o diagnóstico de DA e para monotorizar a eficácia de terapias que visam as alterações no péptido Aβ. Plasma é barato e fácil de colher, permitindo a recolha rotineira de amostras. No entanto, oferece vários desafios devido ao seu alto teor proteico e devido à presença de anticorpos de interferência. Estes anticorpos influenciam manifestamente a immunodetecção dos péptidos Aβ, impedindo a sua correcta quantificação. O principal objectivo deste estudo foi então quantificar de forma precisa e correcta os níveis de péptidos Aβ (Aβx-37, Aβx-38, Aβx-40 and Aβx-42) presentes no plasma de caninos e correlacionar o efeito de inibidores de β-secretase nos níveis de péptido Aβ no plasma com o efeito dos mesmos compostos nos níveis de Aβ no LCR. Uma quantificação precisa do péptido Aβ1-40 em plasma foi alcançado com o pré-tratamento das amostras de plasma canino com agentes de bloqueamento de interferências. Os inibidores de β-secretase mostraram diminuir os níveis de Aβ40 no plasma e no LCR. Foi encontrada correlação entre o efeito destes compostos nos dois fluidos.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the world’s major cause of dementia. The neuropathological hallmarks of this disorder are the extracellular accumulation of amyloid beta (Aβ) peptides and the intracellular aggregation of hyperphosphorylated tau. Aβ peptides are formed through the cleavage of APP by β- and γ-secretase in the amyloidogenic pathway and accumulation of Aβ in brain is suggested to be the primary event in AD. Nowadays, only symptomatic treatments are available for AD patients. The search for disease-modifying drugs is an active area in the pharmaceutical industry, and some compounds are being tested in clinical trials. Several targets involved in the production and clearance of Aβ peptides are being studied as therapeutic targets. β-secretase inhibitor (BACEi) compounds decrease the generation of longer and more prone to self-aggregation Aβ peptides, such as Aβ1-42. Biomarkers allow not only to predict and observe the progression of AD but also to monitor the efficacy of disease-modifying drugs. Currently available biomarkers for diagnosis and treatment efficacy evaluation include biochemical markers in CSF and brain imaging. However, both techniques have limitation: the collection of CSF is an invasive procedure with possible side effects to patients and brain imaging is an expensive technique. The measurement of Aβ peptides in plasma has been suggested as an inexpensive, non-invasive tool to diagnose AD and to monitor Aβ-modifying therapies. Plasma is easy and cheap to collect allowing routine sampling over time. Nevertheless, this fluid offers several challenges of its own due its high protein content and the presence of interfering antibodies. These antibodies can interfere with the Aβ immunoassays, leading to an inaccurate measurement of Aβ levels. The main purpose of this study was to accurately measure Aβ peptide (Aβx-37, Aβx-38, Aβx-40 and Aβx-42) level in plasma samples from canines, and correlate the effect of different Aβ-modifying compounds (BACEi) in plasma with the effect of the same compounds in CSF. An accurate measurement of Aβ1-40 peptide in plasma was achieved with the pre-treatment of dog plasma samples with interference blocking agents. BACE inhibitors were shown to decrease Aβ40 levels in both plasma and CSF. A correlation between the effects of these compounds in the two fluids was found.
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Maibach-Wulf, Katharina. "Über die Interaktionen des zellulären Prion-Proteins (PrPc) mit relevanten Proteinen der Alzheimer Erkrankung." Doctoral thesis, 2014. http://hdl.handle.net/11858/00-1735-0000-0022-5F0C-F.
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Treiber, Hannes. "Die Rolle der Beta-Sekretase bei der Myelinisierung im Zentralen Nervensystem." Doctoral thesis, 2014. http://hdl.handle.net/11858/00-1735-0000-0022-5E84-5.
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BACE1, die beta-Sekretase, spielt eine zentrale Rolle bei der Entstehung von Amyloid, einem charakteristischen histopathologischen Merkmal der Alzheimer-Demenz. Die physiologische Funktion von BACE1 ist unklar. Neuere Studien zeigten eine Rolle bei der Myelinisierung. Die vorliegende Arbeit untersucht die Rolle von BACE1 bei der Myelinisierung im Zentralen Nervensystem. Zusammenfassend zeigt die Studie keinen Einfluss einer BACE1-Inhibiton auf die primäre Ausprägung der Myelinscheiden im Corpus callosum. Sie widerspricht damit der Hypothese, dass BACE1 via Neuregulin-1-Prozessierung notwendig für die Myelinisierung im ZNS ist. Ob es sich dabei um lokale Differenzen einzelner anatomischer Regionen handelt muss in weiteren Studien untersucht werden. Zudem zeigt diese Arbeit einen kleinen, aber signifikanten Einfluss von BACE1 bei der Remyelinisierung im Corpus callosum nach Cuprizonebehandlung auf.