Dissertations / Theses: 'Alzheimer's disease; Amyloid precursor protein'

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Dunbar, Charlotte Emily. "Fe65-amyloid precursor protein signalling and Alzheimer's disease." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/fe65amyloid-precursor-protein-signalling-and-alzheimers-disease(7a7a8605-20a7-4a78-9048-c47b3cb324ce).html.

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Deposition of Aβ in amyloid plaques and accumulation of hyperphosphorylated tau in neurofibrillary tangles are hallmark pathologies of Alzheimer’s disease. Changes in APP processing alter Aβ generation and are likely to affect APP function, which may also contribute to Alzheimer’s disease. APP binds to adaptor protein Fe65 and one proposed function of this complex is to signal to the nucleus to regulate gene transcription. However, the mechanisms that regulate APP-Fe65 binding and the genes regulated by this pathway are poorly understood. Phosphorylation is a common mechanism for regulating protein-protein interactions and Fe65 is phosphorylated by several kinases, including ERK1/2. The first hypothesis investigated in this thesis is that BDNF signalling, which leads to ERK1/2 activation, stimulates Fe65 phosphorylation to regulate its binding to APP. BDNF was found to induce ERK1/2-dependent phosphorylation of Fe65 and, in a variety of assays including the use of phosphomutants, BDNF-induced phosphorylation of Fe65 was shown to inhibit the binding of Fe65 to APP. Unpublished next generation sequencing of Fe65 knockout mouse brains suggested that Fe65 may affect the wnt signalling pathway, which regulates GSK3β activity. GSK3β is a kinase involved in the hyperphosphorylation of tau in Alzheimer’s disease. The second hypothesis tested in this thesis is that Fe65 regulates genes that are linked to GSK3β activity and tau phosphorylation. RT-qPCR carried out on Fe65 knockout mouse brains and siRNA-treated rat cortical neurons found that expression of wnt receptor Fzd-1 was affected by loss of Fe65. Additionally, loss of Fe65 decreased both GSK3β activity and tau phosphorylation. These results show that Fe65 is involved with APP to function in a key process that can be regulated by BDNF, a treatment previously shown to be neuroprotective in Alzheimer’s disease models. Furthermore, they reaffirm the link between APP and Fe65 and link Fe65 to tau phosphorylation, which may be the first step in understanding the relationship between the two hallmark pathologies of Alzheimer’s disease.

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McLoughlin, D. M. "Identification of proteins interacting with the Alzheimer's disease amyloid precursor protein." Thesis, King's College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343724.

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Stephens, David John. "Intracellular processing of the Alzheimer's #beta#-amyloid precursor protein." Thesis, St George's, University of London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362427.

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

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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.

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Prager, Kai. "Investigation of #alpha#-secretase cleavage of amyloid precursor protein." Thesis, Queen's University Belfast, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300994.

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Webster, Marie-Therese. "Studies on the amyloid precursor protein : implication for Alzheimer's disease." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338835.

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Boyce, Susan Gillian. "Amyloid precursor protein subtypes and secretases implicated in Alzheimer's disease." Thesis, Sheffield Hallam University, 2011. http://shura.shu.ac.uk/19378/.

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To date there is no definite understanding to suggest a clear causative route in the events which lead to the neurodegenerative disorder Alzheimer disease (AD) however several proteins have been implicated. Eight proteins that have been implicated in AD have been mapped across seven regions of non-human primate brain tissue from a Macaca fascicularis in this study: APP[770]; APP[751]; APP[695]; ADAM 9, 10 and 17 as alpha-secretases; BACE 1 as beta-secretase and PS1 as gamma-secretase. The APP[695] isoform was found to have the highest levels in the frontal and temporal regions. However, the APP[751] isoform was found to be at the highest level, with very low levels of APP[695] in the soluble fractions of the hippocampus and hypothalamus. Membrane associated levels of alpha-secretases were found to be highest in frontal, temporal, cerebellar, hypothalamus, basal ganglia and hippocampus. The distribution of BACE 1 was found to be low in the frontal and temporal regions in comparison to all the other regions sampled where levels exceeded the levels in the frontal region by over three times. The distribution of gamma-secretase across the regions showed an even distribution with the exception of the hippocampus which had an almost double level in comparison to the other areas sampled. With a relatively high level of the gamma-secretase and gamma-secretase and a concomitant very high level of the APP[kpi] containing subtype APP[751] this would tend to indicate a different sensitivity in the hippocampus and hypothalamus compared to the other regions sampled. The conclusion that may be drawn from these findings is that since the hippocampus and hypothalamus are two of the earliest regions to be affected in AD altered processing of the subtype APP[751] may indicate a regional sensitivity. The culture of NT2/D1 clonal cells with retinoic acid results in the appearance of post-mitotic human neuronal cells. The APP isoforms and secretases present in the brain regions of the Macaca fascicularis have been observed in the NT2 cells as they have been cultured with retinoic acid to obtain the NT2-N neuron-like cells. NT2 cells cultured without retinoic acid produced the sAPP[kpi] subtype in contrast to the cells cultured in the presence of retinoic acid where APP[695] is the predominant subtype. The three secretases of interest in AD were expressed in the NT2 cells and the NT2-N cells similar to the expression in Macaca fascicularis brain tissue. The most notable difference between the brain tissue and NT2/NT2-N cells was to be seen in the expression of BACE 1 as beta-secretase. In the NT2/NT2-N cells BACE 1 appears to be expressed as a stable and high molecular weight form not seen in the Macaca fascicularis brain tissue. The gamma-secretase expression in NT2/NT2-N cells represented by immuno-blotting with an antibody raised against Presenilinl reflected the position seen in the brain tissue. The secretases and APP subtypes in the NT2-N cells most closely reflect the expression found in the hippocampus and hypothalamus of the Macaca fascicularis brain tissue and therefore are a good cellular model for AD.

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McAllister, Cecilia. "An investigation of the proteolytic processing of amyloid precursor protein." Thesis, Queen's University Belfast, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300614.

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Newton, Jillian Rose Ann. "Strategies for the examination of Alzheimer's disease amyloid precursor protein isoforms." Thesis, Sheffield Hallam University, 2004. http://shura.shu.ac.uk/20769/.

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The principal aim of this research project has been the utilisation of various proteomic techniques in the investigation of the Alzheimer's disease amyloid precursor protein (APP) isoforms, namely APP[695], APP[751] and APP[770]. One of the most noticeable pathological characteristics of Alzheimer's disease is the presence of neuritic plaques in brain tissue. The chief protein constituent of neuritic plaques is the beta amyloid peptide. This peptide is proteolytically cleaved from APP, as such the interest in APP isoforms is great and a rapid detection method for the presence of each isoform would be a huge advantage to the research effort with regards to the determination and concentration in both diseased and non-diseased states. Two-dimensional gel electrophoresis and peptide mass fingerprinting are two of the most important techniques in the proteomics arena and both are investigated fully in this work. Retinoic acid induced Ntera 2 cells, derived from a human teratocarcinoma cell line, were the in vitro source of APP. Initial isolation of APP was performed by immunoprecipitation, using a monoclonal antibody raised to amino acids 1-17 of the beta-amyloid peptide sequence, which is present in all three alpha secretase cleaved isoforms of interest. The next step was to separate whole APP into its isoform components by two-dimensional gel electrophoresis. The resulting protein spots were then subjected to peptide mass fingerprinting employing the different digest reagents, trypsin, endoproteinase Asp-N and formic acid. Initial distinction between the APP isoforms could be seen upon examination of theoretical in silica digests using the various digest reagents mentioned. The in silica digests revealed peptides unique to each isoform that in theory could be used as indicators of isoform presence.

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10

Golde, Todd Eliot. "Analysis of the beta amyloid precursor protein mRNAs in Alzheimer's disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 1991. http://rave.ohiolink.edu/etdc/view?acc_num=case1056572599.

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Ostrowski, Stephen M. "Pleiotropic mechanisms of statin action in Alzheimer's Disease." Cleveland, Ohio : Case Western Reserve University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1190669698.

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Holliman, Damian. "Studies of the amyloid precursor protein in cultured cells and transgenic mice." Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244581.

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13

Flood, Fiona. "Alzheimer's disease-related amyloid precursor protein and presenilin genes : normal function and pathophysiology /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-050-8/.

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Lu, Daniel C. "Intracytoplasmic caspase cleavage of [beta]-amyloid precursor protein : implications for Alzheimer's disease /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2001. http://wwwlib.umi.com/cr/ucsd/fullcit?p3022210.

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Palmert, Mark Raney. "The beta amyloid protein precursor of Alzheimer's disease: Analysis of mRNAs and protein products." Case Western Reserve University School of Graduate Studies / OhioLINK, 1990. http://rave.ohiolink.edu/etdc/view?acc_num=case1054920188.

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16

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.

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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.

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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.

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Selivanova, Alexandra. "Intracellular dynamics of Alzheimer disease-related proteins /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-234-7/.

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Gibbons-Frendo, Sam. "The amyloid precursor protein and the axonal transport of mitochondria in Alzheimer's disease." Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/the-amyloid-precursor-protein-and-the-axonal-transport-of-mitochondria-in-alzheimers-disease(ddb5cea4-2469-4104-ad0c-cd545581a45c).html.

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Defects in axonal transport are an early pathological event in Alzheimer’s disease, suggesting that damage to the transport process could contribute to the disease. A large number of cargoes are transported through axons and mitochondria represent a particularly important cargo. This is because mitochondria need to be distributed to axonal regions where their functions in ATP synthesis and the regulation of calcium homeostasis are required. This is particularly important in synaptic regions where neurons have high energy and calcium-buffering requirements. As such, mitochondria are transported bi-directionally through axons and this movement is responsive to physiological stimuli. has been shown to disrupt axonal transport of mitochondria but these studies involved application of synthetic Ap to neuronal culture media. In this thesis, the effect of the expression of a familial Alzheimer’s disease mutant amyloid precursor protein (APP) that increases Ap production (the APP Swedish mutant) on axonal transport of mitochondria was studied. This approach represents a more physiological route for studying the effect of APP and Ap on axonal transport. Mitochondrial axonal transport was monitored in cultured neurons via time-lapse microscopy. Expression of APPswe led to a selective disruption of anterograde but not retrograde axonal transport of mitochondria. Mitochondria are transported anterogradely on the microtubule based molecular motor kinesin-1. Mitochondria attach to kinesin-1 via the outer mitochondrial membrane protein Mirol and the adaptor protein TRAK1. Defective mitochondrial transport induced by APPswe did not affect the binding of kinesin-1 to mitochondria. Rather, APPswe caused mitochondria with associated Mirol, TRAKl and kinesin-1 to detach from the microtubule rails. In order to gain insight into the molecular mechanisms that underlie the APPswe effect on transport and to test potential therapeutic approaches, a number of different Alzheimer’s disease-associated features were experimentally manipulated. In particular, inhibition of APP processing and A|3 production with the y-secretase inhibitor DAPT, inhibition of glycogen synthase kinase-3 and increased tubulin acetylation all rescued the APPswe-induced transport defect. These results provide novel insight into the mechanisms underlying defective axonal transport in Alzheimer’s disease and provide new information on how some proposed Alzheimer’s disease therapeutics might act at a molecular level.

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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.

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21

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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22

Neill, David. "Effects of aluminium and the VAL717ILE mutation on expression and processing of amyloid precursor protein." Thesis, Queen's University Belfast, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239213.

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Chapman, Sara. "The role of the wingless or WNT pathway on processing of the amyloid precursor protein." Thesis, King's College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249435.

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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.

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25

Nilsson, Tatjana. "Amyloid precursor protein: cellular studies and animal models /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-832-0/.

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Reguengo, Sérgio Paulo Soares. "Amyloid precursor protein Thr668 phosphodependent complexes." Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/15470.

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Mestrado em Biomedicina Molecular
Alzheimer’s disease has as one of its characteristic hallmarks, deposits of a toxic peptide Aβ, known as senile plaques (SP). The toxic peptide is produced via complex intracellular pathways and cleavage of the Alzheimer’s Amyloid Precursor Protein (APP). Several aspects are key to APP processing. Among them, the proteins that bind to APP and form different complexes, which are functionally relevant. Recent studies have shown that the phosphorylation state of APP itself is determinant with respect to the protein complexes formed. Thus the protein’s phosphorylation state ultimately determines its own fate, the rate of Aβ production and the formation of SPs. It is also noteworthy the patients with Swedish mutation produced 10 times more Aβ. The aim of this thesis is to consider the above mentioned factors, which modulate Aβ production in a unified perspective. That is, to consider how protein phosphorylation affects Aβ production, bearing in mind the phosphorylated state of the protein itself and the complexes that are formed. In order to address these questions, several biological tools have to be available. Hence this thesis set out to prepare the APP Swedish mutations (to produce 10 times more Aβ) on a cDNA which also expressed phosphorylation site mutations on APP Thr668. This was achieved and it was possible to demonstrate that the resulting mutations did in fact produce considerably higher levels of the toxic peptide. Preliminary immunocytochemistry studies allowed for assessment of cellular distribution of the mutants and PP1γ in SHSY5Y cells, and more studies are needed to assess the co-localization of the trimeric protein complex between the APP mutants. PP1γ and Fe65. Therefore additional studies could contribute to a better understanding of the way that Aβ production is influenced by protein complexes regulated by APP phosphorylation.
A Doença de Alzheimer tem como uma das suas características principais, os depósitos do péptido tóxico Aβ, conhecidos como placas senis (PS). O péptido tóxico é produzido por complexas vias intracelulares e clivagens da Proteína Precursora Amiloide (PPA). Vários aspetos são importantes para o processamento da PPA. Entre eles, as proteínas que se ligam à PPA e formam diferentes complexes que são funcionalmente relevantes. Estudos recentes demonstraram que o estado de fosforilação da própria PPA é determinante para a formação desses complexos. Portanto, o estado de fosforilação da PPA determina o seu próprio destino, o rácio de produção de Aβ e a formação de placas senis. É também digno de nota que pacientes com mutação Swedish produzem cerca de 10 vezes mais Aβ. O objetivo desta tese é considerar os fatores acima mencionados que modulam a produção de Aβ numa perspetiva única. Ou seja, considerar como a fosforilação da PPA afeta a produção de Aβ, tendo em conta o próprio estado fosforilado da proteína e os complexos proteicos que dai são formados. De modo a responder a essas questões, várias ferramentas biológicas tem que ser disponibilizadas. Consequentemente, esta tese propõem-se a preparar mutações Swedish na PPA (para produzir 10 vezes mais Aβ), a partir de cDNA da PPA que expressa mutações que imitam a fosforilação da Thr668. Este objetivo foi conseguido e foi possível demonstrar que as referidas mutações produziram níveis consideravelmente altos do péptido tóxico. Estudos preliminares de imunocitoquímica permitiram avaliar a distribuição celular dos mutantes produzidos, bem como da PP1γ em células SH-SY5Y, mas mais estudos são necessários para avaliar a co-localização do complexo proteico trimérico entre os mutantes da PPA, PP1γ e Fe65. Assim sendo, estudos adicionais poderão contribuir para um melhor conhecimento da maneira como a produção de Aβ é influenciada por complexos proteicos regulados pela fosforilação da PPA.

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Ly, Philip T. T. "Glycogen synthase kinase-3 signaling in Alzheimer's disease : regulation of beta-amyloid precursor protein processing and amyloid beta protein production." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/42848.

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Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that plays a part in a number of physiological processes ranging from glycogen metabolism to gene transcription. Recent studies indicated that GSK3 also involved in the formation of Alzheimer’s disease (AD) pathologies: neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles develop when abnormal tau proteins accumulate inside neurons and form insoluble filaments, and amyloid plaques develop when the amyloid β protein (Aβ) accumulates in increasingly insoluble forms. The Aβ peptide is generated through sequential cleavages of the β-amyloid precursor protein by β-secretase (BACE1) and γ-secretase. Accumulation of insoluble Aβ is believed to trigger the initial series of neurodegenerative events leading to AD. Therefore, inhibition of the pathways that lead to Aβ generation will have therapeutic implications for AD treatment. The mechanism by which GSK3 affects APP processing and Aβ production has been controversial. Previous published reports have found differential effects on GSK3-mediated APP processing. This thesis entails a thorough investigation of GSK3’s role in APP processing and Aβ production. First, the therapeutic effects of the anti-convulsant drug, valproic acid (VPA) were tested in AD modeled mice. VPA, a known GSK3 inhibitor could interfere with Aβ production, and rescued memory deficits. In addition to inhibiting GSK3 activity, VPA also stimulate a plethora of signaling cascades. To further our understanding of GSK3’s effect on APP processing, a GSK3 specific pharmacological inhibitor (AR-A014418) and siRNA technologies were used in our systems. With specific GSK3β inhibition, we showed that BACE1-mediated cleavage of APP and Aβ production were reduced. Moreover, GSK3β induced BACE1 gene expression depends on NFκB activity. Additionally, specific inhibition of GSK3 also reduced Aβ production and neuritic plaque formation in AD modeled mice, as well as improved memory functions. Finally, this thesis examined in detail the role of GSK3 in AD pathogenesis. This study demonstrated for the first time that the GSK3β signaling pathway regulates BACE1 transcription and facilitates Aβ production. These findings reinforced the notion that specific GSK3 inhibition is a safe and effective approach for treating AD.

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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.

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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.

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29

Fisher, Linda. "Inflammatory cytokines and NFkB in Alzheimer's disease /." Stockholm : Department of Neurochemistry, Stockholm University, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-990.

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30

Beckett, Caroline. "Mechanistic studies of the amyloid precursor protein intracellular domain (AICO) with implications for Alzheimer's disease." Thesis, University of Leeds, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.634749.

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Proteolytic cleavage of the amyloid precursor protein (APP) by the successive actions of [beta]- and [gamma] secretases produces amyloid-B-peptide (AB), the principal constituent of plaques in Alzheimer's disease (AD). In AD research, therapeutic strategies have heavily focussed on modifying the formation, aggregation and removal of AB. Yet, two decades on, available treatments remain limited and they are palliative, rather than disease modifying. Despite its major importance, the normal physiology of APP, its isoforms and its other biologically active metabolites remain largely unknown. The aim of this study was to investigate the role of the APP intracellular domain (AICD). By analogy with the Notch signalling pathway, AI CD has been proposed to have transcriptional activity although its mechanism of action and the complement of genes regulated remain controversial.

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Taverna, Mara. "Detection of the Alzheimer's disease soluble amyloid precursor protein and modulation of its proteolytic processing." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-177967.

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Lilley, Caroline Elizabeth. "Herpes simplex virus vectors for gene delivery to the CNS : applications in the study of Alzheimer's disease." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326175.

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Taylor, Chanel Jayne, and n/a. "Secreted amyloid precursor protein-alpha modulates hippocampal long-term potentiation, in vivo." University of Otago. Department of Psychology, 2008. http://adt.otago.ac.nz./public/adt-NZDU20081217.144344.

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Alzheimer�s disease (AD) is a neurodegenerative disorder, charaeterised by progressive loss of memory. It is important to understand what factors initiate the onset of AD so that effective therapeutic treatments can be developed to target the precise mechanisms that initiate this disease. Currently, synaptic dysfunction is widely believed to be the first significant alteration preceding the onset of AD, and is thought to be initiated by an intracellular accumulation of amyloid-β (Aβ), or a free radical-induced increase of oxidative stress. As Aβ levels rise during the onset of AD, a concomitant reduction of secreted amyloid precursor protein-α (sAPPα) is observed, as the two proteins exist in equilibrium. Intriguingly, the neuroprotective and neurotrophic properties of sAPPα indicate that it is intimately involved in the physiological pathways of the major hypotheses for the cause of AD, and may also be involved in the mechanisms that underlie learning and memory. Therefore, it is possible that during the onset of AD, the decrease of sAPPα may contribute to synaptic dysfunction by disrupting the mechanisms of synaptic plasticity. Long-term potentiation (LTP) is the leading experimental model for investigating the neural substrate of memory formation, and describes the molecular mechanisms that underlie an increase in the strength of synaptic transmission. The role sAPPα may play in the induction and maintenance of LTP has not previously been addressed in vivo. Therefore, the aim of this thesis was to investigate whether sAPPα affects the induction of LTP in the hippocampus of the anaesthetised rat. The present findings are the first to suggest that sAPPα may modulate the induction of LTP in vivo. Decreasing the function of endogenous sAPPα (with sAPPα-binding antibodies and a pharmacological inhibition of α-secretase) significantly reduced the magnitude of LTP induced in the dentate gyrus. Therefore, the reduction of sAPPα during AD is likely to have a detrimental impact on the mechanisms of synaptic plasticity, and by extension, learning and memory. The present investigation has also found that the application of recombinant, purified sAPPα to the rat hippocampus has an �inverted U-shaped� dose-response effect on the magnitude of LTP. Low concentrations of sAPPα significantly enhanced LTP, supporting previous findings that exogenous sAPPα can facilitate in vitro LTP and enhance memory performance in animals. On the other hand, comparatively high concentrations of sAPPα significantly decreased the magnitude of LTP. This observation is also consistent with previous findings, in which high concentrations of sAPPα have been shown to be less synaptogenic and memory enhancing than lower doses. These results are the first to suggest that sAPPα modulates in vivo synaptic plasticity, and have important implications for the development of strategies to treat AD.

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Pasternack, Jennifer Martine. "The Alzheimer's disease beta amyloid protein precursor: Analysis of the carboxyl terminus of its soluble derivatives." Case Western Reserve University School of Graduate Studies / OhioLINK, 1992. http://rave.ohiolink.edu/etdc/view?acc_num=case1060094123.

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35

Lebson, Lori Ann. "Monocytes as gene therapy vectors for the treatment of Alzheimer's disease." [Tampa, Fla] : University of South Florida, 2008. http://purl.fcla.edu/usf/dc/et/SFE0002793.

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36

Andrew, Robert. "Differential proteolysis of the amyloid precursor protein isoforms : the role of cellular location and protein-protein interactions." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/differential-proteolysis-of-the-amyloid-precursor-protein-isoforms-the-role-of-cellular-location-and-proteinprotein-interactions(5390e8fa-fc5e-4357-8109-cb2bb1c49212).html.

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Dementia, the most common cause of which is Alzheimer's disease (AD), currently affects 850,000 people in the UK, a figure set to rise to over 1 million by 2025. There is currently no disease modifying therapy available to slow or halt this progressive disease. Current understanding of AD implicates the neurotoxic amyloid-β (Aβ) peptide as the primary initiator in a cascade of events leading to the neuronal cell death and brain atrophy associated with the disease. Therefore, inhibiting the production or enhancing the clearance of Aβ within the brain has become a major target for the production of disease modifying therapeutics. Aβ is produced by brain cells through the sequential proteolytic cleavage of a larger transmembrane protein known as the amyloid precursor protein (APP) by β- and γ-secretases. Several aspects of APP physiology can influence its proteolysis, and thus Aβ production, including the isoform of APP which is expressed, its trafficking and subcellular location and its physical interactions with other proteins in the cellular environment. Here we have investigated the influence of subcellular trafficking and location and protein-protein interactions on the differential proteolysis of two APP isoforms, APP695 and APP751 in a neuroblastoma cell line. We have shown that APP751 undergoes less amyloidogenic proteolysis than APP695 and that retention within the early secretory pathway may contribute to this difference. APP751 shows higher co-localisation to the trans-Golgi network than APP695 in immunofluorescence microscopy studies, while addition of a mutation which causes APP proteolysis in the secretory pathway reduces the large difference in amyloidogenic proteolysis of these two isoforms. Targeting APP endocytosis from the cell surface, thought to be a key determinant in Aβ generation, effects APP isoform proteolysis and Aβ production to a similar extent in both the APP isoforms suggesting differences in proteolysis occur before this trafficking event. We also show by immunoblot analysis that the APP isoforms may be differentially cleaved by proteases other than β- and γ-secretase to produce recently identified proteolytic fragments. Using a liquid chromatography - tandem mass spectrometry approach coupled to prior stable isotope labelling of amino acids in cell culture (SILAC), we have identified the interactomes of the two APP isoforms in our model system. Gene ontology analysis identified enrichment of nuclear and mitochondrial proteins specifically in the APP695 interactome. Using siRNA mediated protein knockdown, we have shown interactions with Fe65 and ataxin-10 specifically influence Aβ generation from the APP695 isoform. Fe65 alters proteolysis at the rate limiting β-secretase cleavage step, while ataxin-10 alters proteolysis by γ-secretase. Interaction with growth-associated protein 43 specifically influences Aβ generation from the APP751 isoform, altering proteolysis at the γ-secretase step. Finally we have shown that recently discovered familial AD-linked mutation and protective mutation within the Aβ region of the APP protein have consistent effects on APP proteolysis in both the APP isoforms.

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Fiorelli, Tina N. "Proteolytic Processing of the Amyloid Precursor Protein During Apoptosis and Cell Cycle: Implications for Alzheimer's Disease." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4486.

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Alzheimer's disease is characterized by the presence of amyloid plaques, made up primarily of Aϐ peptides, and neurofibrillary tangles, containing hyperphosphorylated tau. Aϐ is generated by sequential proteolysis of the amyloid precursor protein (APP) by beta and gamma secretases. The leading hypothesis of Alzheimer's disease pathogenesis is the amyloid cascade hypothesis, which suggests that amyloid is central to the disease process. However, tau pathology correlates more closely with cognitive dysfunction and follows a predictable anatomical course through the brain. We hypothesize that if Aϐ is upstream of tau pathology and tau pathology follows this predictable course through the brain, Aϐ production may also propagate through the brain in an anatomical fashion. In order to investigate this possibility, we examined two broad cellular processes induced in cells when exposed to Aϐ, p53-dependent apoptosis and cell cycle activation. We report that p53-dependent apoptosis is associated with a decrease in the Aϐ and sAPP-alpha and an increase in an alternative, caspase-cleaved fragment of APP, resulting from an apparent cleavage in the near extracellular domain of APP. Mitosis is associated with the phosphorylation of both tau and APP, and increased production of Aϐ. Our results indicate that while p53-dependent apoptosis is not associated with increased amyloidogenesis, cell cycle activation increases Aϐ production and may play a role in disease propagation. Together, these findings suggest various treatment approaches, including cell cycle inhibition and disruption of APP endocytosis, which may decrease amyloidogenic processing. Continued research into these potential approaches, coupled with earlier detection of the disease process, could lead to promising treatments for Alzheimer's disease.

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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’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

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Zhang, Yu-Qian. "INDUCTION OF THE HEAT SHOCK RESPONSE TO PROTECT AGAINST POLYGLUTAMINE DISEASES AND THE ROLE OF PROTEIN SUMOYLATION IN LAMINOPATHIES AND ALZHEIMER'S DISEASE." UKnowledge, 2008. http://uknowledge.uky.edu/gradschool_diss/632.

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Heat shock proteins function as molecular chaperones which help protein folding and prevent protein aggregation. My study shows that celastrol, a pharmacological compound capable of up-regulating the levels of heat shock proteins, inhibits cell death and protein aggregation caused by expanded polyglutamine containing protein, and the protective effects of celastrol are dependent on heat shock factor 1. These results suggest the potential of celastrol as a therapeutic agent in the treatment of polyglutamine diseases. Sumoylation is a protein modification which plays diverse roles in regulating the target proteins. My study shows that lamin A is a target of protein sumoylation, and two lamin A mutants associated with familial dilated cardiomyopathy, E203G and E203K, exhibit decreased sumoylation. My results also indicate that sumoylation is important for the normal localization of lamin A, and support a role for altered sumoylation in the underlying molecular mechanism of cardiomyopathies associated with the E203G/E203K lamin A mutations. In the third project, my results show that amyloid precursor protein is another target of SUMO modification, and sumoylation of amyloid precursor protein reduces the levels of amyloid β aggregates, which are the primary causative factor for Alzheimer’s disease. My results provide a new mechanism for the generation of amyloid β, and indicate the potential of up-regulating activity of the cellular sumoylation machinery as an approach against Alzheimer’s disease. My results also provide the first demonstration that SUMO E2 enzyme exists in the lumen of the endoplasmic reticulum, extending the sub-cellular reach of sumoylation to include the regulation of proteins in secretory pathways.

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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.

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Rice, Heather Caroline. "Regulation of the Proteolytic Processing and Function of Amyloid Precursor Protein by Candidate Ligands." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11014.

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Despite intense interest in the proteolysis of Amyloid Precursor Protein (APP) in Alzheimer’s disease (AD), how the normal processing and function of this type I receptor-like glycoprotein is regulated remains ill-defined. APP is reported to function in neurodevelopment, including migration of neuronal precursor cells into the cortical plate. In recent years, several candidate ligands for APP, including F-spondin, Reelin, \(\beta1\) Integrin, Contactins, and Lingo-1 have been reported. However, a cognate ligand for APP that regulates its function or processing has yet to be widely confirmed in multiple laboratories. First, in an unbiased approach to reveal novel ligands, Pancortin was identified by a mass spectrometry-based screen for factors that bind to the APP ectodomain in rodent brain. Each of the Pancortin isoforms was confirmed to interact with APP. However, only specific Pancortin isoforms reduced \(\beta\)-secretase but not \(\alpha\)-secretase cleavage of endogenous APP. Using in utero electroporation to overexpress or knockdown Pancortin isoforms in rodent cortex, a previously unidentified role for Pancortin in cortical cell migration with evidence for a functional interaction with APP was discovered. Next, I developed new assays in an effort to confirm a role for one or more of the published candidate ligands in regulating APP ectodomain shedding in a biologically relevant context. A comprehensive quantification of APPs\(\alpha\) and APPs\(\beta\), the immediate products of secretase processing, in both non-neuronal cell lines and primary neuronal cultures expressing endogenous APP yielded no evidence that any of these published candidate ligands stimulate ectodomain shedding. Rather, Reelin, Lingo-1 and Pancortin emerged as the most consistent ligands for significantly inhibiting ectodomain shedding. These studies clarify mechanisms regulating the function and processing of APP, which is needed to understand consequences of chronically altering APP proteolysis to treat AD and to develop new potential drug targets.

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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.

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Smotherman, Jesse M. "The Impact of Causative Genes on Neuropsychological Functioning in Familial Early-Onset Alzheimer's Disease: A Meta-Analysis." Thesis, University of North Texas, 2017. https://digital.library.unt.edu/ark:/67531/metadc984161/.

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Mutations of three genes encoding amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) have been shown to reliably result in familial early-onset Alzheimer's disease (FAD); a rare, but catastrophic, subtype of Alzheimer's disease (AD) marked by symptom emergence before age 65 as well as accelerated cognitive deterioration. The current study represents the first known meta-analysis on the association of APP, PSEN1 or PSEN2 on neurocognitive variables. A total of 278 FAD mutation-carriers (FAD-MC) and 284 cognitively healthy non-mutation-carriers (NC) across 10 independent investigations meeting inclusion criteria were chosen for the current meta-analysis (random effects design). Findings revealed an overarching trend of poorer performance by FAD-MC individuals compared to NC individuals across the majority of cognitive domains identified. Significant differences in effect sizes suggested FAD-MC individuals exhibited worse performance on measures of attention, explicit memory, fluency, primary memory, verbal, and visuospatial functioning. Findings indicative of differential sensitivity to cognitive domain impairments across FAD-MC and NC groups inform neuropsychological descriptions of individuals in preclinical phases of FAD.

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Krüger, J. (Johanna). "Molecular genetics of early-onset Alzheimer's disease and frontotemporal lobar degeneration." Doctoral thesis, University of Oulu, 2010. http://urn.fi/urn:isbn:9789514263156.

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Abstract Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are the two most common neurodegenerative diseases leading to early onset dementia (< 65 years). Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes cause a proportion of familial early-onset AD (eoAD), while the microtubule-associated protein tau (MAPT) and progranulin (PGRN) mutations have been identified in FTLD patients. Only a few PSEN1 and APP mutations have previously been found in Finnish AD patients, and one MAPT mutation in a FTLD family, while the role of PGRN in Finnish FTLD patients is unknown. Increasing evidence suggests that mitochondrial dysfunction and oxidative stress also play an important role in neurodegenerative diseases. The aim here was to investigate the genetics of eoAD and FTLD in the population of the province of Northern Ostrobothnia, Finland. Sequencing analysis of the APP, PSEN1 and PSEN2 genes was performed to determine whether mutations in these genes could be detected. The MAPT and PGRN genes were analysed in the FTLD patients by sequencing and MAPT haplotypes were determined. The contributions of mtDNA and its maintenance enzymes to eoAD and FTLD were studied by comparing the frequencies of mtDNA haplogroups and their clusters between the patient groups and controls and by screening for the five common POLG1 mutations (T251I, A467T, P587L, W748S, Y955C), two common mtDNA mutations (m.3243A>G, m.8344A>G) and mutations in the PEO1 and ANT1 genes. This is the first report of a significant association between the mtDNA haplogroup cluster IWX and FTLD. The H2 MAPT haplotype was also associated with FTLD in our cohort. No significant differences in the frequencies of the mtDNA haplogroups were observed between the eoAD patients and controls, nor were there any pathogenic mutations detected in the genes analysed. The findings suggest that possession of the mtDNA haplogroup cluster IWX and the H2 MAPT haplotype may be possible risk factors for FTLD in our cohort. The absence of any pathogenic mutations in the MAPT, PGRN, APP or PSEN genes in our series, together with the previous reports of only a few mutations found in this region, supports a minor role for these genes in the aetiology of eoAD and FTLD in Northern Ostrobothnia and indicates that this population may have its own genetic features. There may be other, still unknown genetic factors to be discovered, that explain familial diseases in the region.

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Li, Xiaoman. "Study on memapsin 2 cleavage properties and its interacting proteins." Oklahoma City : [s.n.], 2010.

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Kirouac, Lisa. "The Concerted Regulation of Intracellular Signaling by Amyloid Precursor Protein and Aβ Peptide." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6278.

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It is widely accepted that A-beta (Aβ) generated from amyloid precursor protein (APP) oligomerizes and fibrillizes to form neuritic plaques in the Alzheimer’s disease (AD) brain, yet little is known about the contribution of APP preceding AD pathogenesis. Our data presented here suggest that APP has a functional role in cell cycle regulation and proliferation. First, we demonstrat that APP is pathologically phosphorylated at Thr668 and that P-APP localizes to the centrosomes. Furthermore, P-APP is proteolytically processed in a cell cycle -dependent manner to generate its pathogenic metabolites. Using Stable Isotope Labeling by Amino Acids in Culture (SILAC) and mass spectrometry analyses, we also show that expression of APP results in the expression of proliferation-associated proteins and the phosphorylation of proteins associated with cell cycle regulation and transcription. Here, we demonstrate that APP expression and oligomeric Aβ42 elicit Ras/ERK signaling cascade and glycogen synthase kinase3 (GSK3) activation. Both ERK and GSK3 are known to induce hyperphosphorylation of tau and of APP at Thr668, and our findings suggest that aberrant signaling by APP facilitates these events. Supporting this notion, analysis of human brain samples show increased expression of Ras, activation of GSK3 and phosphorylation of APP and tau, which correlate with Aβ levels in the AD brains. Furthermore, treatment of primary rat neurons with Aβ recapitulate these events and show enhanced Ras-ERK signaling, GSK3 activation, upregulation of cyclin D1, and phosphorylation of APP and tau. The finding that Aβ induces Thr668 phosphorylation on APP, which we show enhances APP proteolysis and Aβ generation, denotes a vicious feed-forward mechanism by which APP and Aβ promote tau hyperphosphorylation and neurodegeneration in AD. Based on these results we hypothesize that aberrant proliferative signaling by APP plays a fundamental role in AD neurodegeneration and an inhibition of this would impede the mitotic catastrophe and neurodegeneration observed in AD.

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Maesako, Masato. "Exercise is more effective than diet control in preventing high fat diet-induced β-amyloid deposition and memory deficit in amyloid precursor protein transgenic mice." 京都大学 (Kyoto University), 2014. http://hdl.handle.net/2433/188709.

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英和, 東出, and Hidekazu Higashide. "Roles of the GXXXG motif in amyloid precursor protein for its dimerization and amyloid β production." Thesis, https://doors.doshisha.ac.jp/opac/opac_link/bibid/BB13080173/?lang=0, 2018. https://doors.doshisha.ac.jp/opac/opac_link/bibid/BB13080173/?lang=0.

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アルツハイマー病の原因物質とされるAβの前駆体C99にはGXXXGモチーフ(以下モチーフ)が存在し、二量体形成に関与してAβ産生に影響を及ぼすとされる。そこでアミノ酸置換によりモチーフのないC99を調製し、その二量体形成とAβ産生への影響を検討した。その結果、モチーフは二量体形成には必要でないこと、Aβ産生を担う酵素の切断を制御する可能性が示された。以上より、モチーフが元来言われていた二量体形成よりも、Aβ産生に強く影響を及ぼすことを示唆している。
Substitutions in GXXXG motifs did not significantly alter C99 dimerization, decreased the production of long Aβ species and increased short Aβ species, and decreased the ratios of precursor/product. In conclusion, my data indicate that GXXXG motifs of C99 are not crucial for the formation of C99 dimers. My findings might be useful for a development of new ways of therapeutic interventions. Because the amino acid substitutions in GXXXG motifs reduced the levels of amyloidogenic Aβ production, drugs targeted to GXXXG motifs would reduce the production of substances of great interest in the field of Alzheimer neuropathology, thereby inhibiting the formation of amyloid plaques.
博士(理学)
Doctor of Philosophy in Science
同志社大学
Doshisha University

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Cai, Xiao-Dan. "Altered Production of Aβ by Mutations of the Amyloid Protein Precursor Linked to Familial Alzheimer’s Disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 1994. http://rave.ohiolink.edu/etdc/view?acc_num=case1061229536.

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Taverna, Mara [Verfasser], and Stefan [Akademischer Betreuer] Lichtenthaler. "Detection of the Alzheimer's disease soluble amyloid precursor protein and modulation of its proteolytic processing / Mara Taverna. Betreuer: Stefan Lichtenthaler." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1064464424/34.

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Dissertations / Theses on the topic 'Alzheimer's disease; Amyloid precursor protein'

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