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Littérature scientifique sur le sujet « AMYLOID, APP, ABETA, ALZHEIMER »
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Articles de revues sur le sujet "AMYLOID, APP, ABETA, ALZHEIMER"
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Xie, Zhongcong, Yuanlin Dong, Uta Maeda, Paul Alfille, Deborah J. Culley, Gregory Crosby et Rudolph E. Tanzi. « The Common Inhalation Anesthetic Isoflurane Induces Apoptosis and Increases Amyloid β Protein Levels ». Anesthesiology 104, no 5 (1 mai 2006) : 988–94. http://dx.doi.org/10.1097/00000542-200605000-00015.
Texte intégralRésumé :
Background The common inhalation anesthetic isoflurane has previously been reported to enhance the aggregation and cytotoxicity of the Alzheimer disease-associated amyloid beta protein (Abeta), the principal peptide component of cerebral beta-amyloid deposits. Methods H4 human neuroglioma cells stably transfected to express human full-length wild-type amyloid precursor protein (APP) were exposed to 2% isoflurane for 6 h. The cells and conditioned media were harvested at the end of the treatment. Caspase-3 activation, processing of APP, cell viability, and Abeta levels were measured with quantitative Western blotting, cell viability kit, and enzyme-linked immunosorbent assay sandwich. The control condition consisted of 5% CO2 plus 21% O2 and balanced nitrogen, which did not affect caspase-3 activation, cell viability, APP processing, or Abeta generation. Results Two percent isoflurane caused apoptosis, altered processing of APP, and increased production of Abeta in H4 human neuroglioma cell lines. Isoflurane-induced apoptosis was independent of changes in Abeta and APP holoprotein levels. However, isoflurane-induced apoptosis was potentiated by increased levels of APP C-terminal fragments. Conclusion A clinically relevant concentration of isoflurane induces apoptosis, alters APP processing, and increases Abeta production in a human neuroglioma cell line. Because altered processing of APP leading to accumulation of Abeta is a key event in the pathogenesis of Alzheimer disease, these findings may have implications for use of this anesthetic agent in individuals with excessive levels of cerebral Abeta and elderly patients at increased risk for postoperative cognitive dysfunction.
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Henriques, A. G., S. I. Vieira et O. A. B. da Cruz e. Silva. « Abeta Induces Abnormal Cytoskeletal Dynamics which are Reversible Upon Peptide Removal ». Microscopy and Microanalysis 18, S5 (août 2012) : 23–24. http://dx.doi.org/10.1017/s1431927612012779.
Texte intégralRésumé :
Alzheimer´s disease (AD) is characterized by extensive neuronal loss in brain areas related to memory and cognitive functions. Central to the neurodegenerative process is a peptide termed Abeta. The latter is the main component of senile plaques, one of the histopathological hallmarks of AD, and derives from proteolytic processing of the Alzheimer´s amyloid precursor protein (APP). Among the alterations induced by Abeta is increased cellular oxidative stress, imbalanced protein phosphorylation and cytoskeletal abnormalities, all factors that contribute to neuronal death.
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Kirkitadze, Marina D., et Anna Kowalska. « Molecular mechanisms initiating amyloid beta-fibril formation in Alzheimer's disease. » Acta Biochimica Polonica 52, no 2 (31 mai 2005) : 417–23. http://dx.doi.org/10.18388/abp.2005_3454.
Texte intégralRésumé :
The deposition of aggregated amyloid beta-protein (Abeta) in the human brain is a major lesion in Alzheimer' disease (AD). The process of Abeta fibril formation is associated with a cascade of neuropathogenic events that induces brain neurodegeneration leading to the cognitive and behavioral decline characteristic of AD. Although a detailed knowledge of Abeta assembly is crucial for the development of new therapeutic approaches, our understanding of the molecular mechanisms underlying the initiation of Abeta fibril formation remains very incomplete. The genetic defects responsible for familial AD influence fibrillogenesis. In a majority of familial cases determined by amyloid precursor protein (APP) and presenilin (PS) mutations, a significant overproduction of Abeta and an increase in the Abeta42/Abeta40 ratio are observed. Recently, it was shown that the two main alloforms of Abeta have distinct biological activity and behaviour at the earliest stage of assembly. In vitro studies demonstrated that Abeta42 monomers, but not Abeta40, form initial and minimal structures (pentamer/hexamer units called paranuclei) that can oligomerize to larger forms. It is now apparent that Abeta oligomers and protofibrils are more neurotoxic than mature Abeta fibrils or amyloid plaques. The neurotoxicity of the prefibrillar aggregates appears to result from their ability to impair fundamental cellular processes by interacting with the cellular membrane, causing oxidative stress and increasing free Ca(2+) that eventually lead to apoptotic cell death.
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Nawrot, Barbara. « Targeting BACE with small inhibitory nucleic acids - a future for Alzheimer's disease therapy ? » Acta Biochimica Polonica 51, no 2 (30 juin 2004) : 431–44. http://dx.doi.org/10.18388/abp.2004_3582.
Texte intégralRésumé :
beta-Secretase, a beta-site amyloid precursor protein (APP) cleaving enzyme (BACE), participates in the secretion of beta-amyloid peptides (Abeta), the major components of the toxic amyloid plaques found in the brains of patients with Alzheimer's disease (AD). According to the amyloid hypothesis, accumulation of Abeta is the primary influence driving AD pathogenesis. Lowering of Abeta secretion can be achieved by decreasing BACE activity rather than by down-regulation of the APP substrate protein. Therefore, beta-secretase is a primary target for anti-amyloid therapeutic drug design. Several approaches have been undertaken to find an effective inhibitor of human beta-secretase activity, mostly in the field of peptidomimetic, non-cleavable substrate analogues. This review describes strategies targeting BACE mRNA recognition and its down-regulation based on the antisense action of small inhibitory nucleic acids (siNAs). These include antisense oligonucleotides, catalytic nucleic acids - ribozymes and deoxyribozymes - as well as small interfering RNAs (siRNAs). While antisense oligonucleotides were first used to identify an aspartyl protease with beta-secretase activity, all the strategies now demonstrate that siNAs are able to inhibit BACE gene expression in a sequence-specific manner, measured both at the level of its mRNA and at the level of protein. Moreover, knock-down of BACE reduces the intra- and extracellular population of Abeta40 and Abeta42 peptides. An anti-amyloid effect of siNAs is observed in a wide spectrum of cell lines as well as in primary cortical neurons. Thus targeting BACE with small inhibitory nucleic acids may be beneficial for the treatment of Alzheimer's disease and for future drug design.
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Tanghe, An, Annelies Termont, Pascal Merchiers, Stephan Schilling, Hans-Ulrich Demuth, Louise Scrocchi, Fred Van Leuven, Gerard Griffioen et Tom Van Dooren. « Pathological Hallmarks, Clinical Parallels, and Value for Drug Testing in Alzheimer's Disease of the APP[V717I] London Transgenic Mouse Model ». International Journal of Alzheimer's Disease 2010 (2010) : 1–9. http://dx.doi.org/10.4061/2010/417314.
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The APP[V717I] London (APP-Ld) mouse model recapitulates important pathological and clinical hallmarks of Alzheimer's disease (AD) and is therefore a valuable paradigm for evaluating therapeutic candidates. Historically, both the parenchymal and vascular amyloid deposits, and more recently, truncated and pyroglutamate-modified Abet species, are perceived as important hallmarks of AD-pathology. Late stage symptoms are preceded by robust deficits in orientation and memory that correlate in time with Abeta oligomerization and GSK3-mediated phosphorylation of endogenous murine Tau, all markers that have gained considerable interest during the last decade. Clinical parallels with AD patients and the value of the APP-Ld transgenic mouse model for preclinicalin vivotesting of candidate drugs are discussed.
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Tadic, Jelena, Julia Ring, Andrea Jerkovic, Selena Ristic, Marta Maglione, Jörn Dengjel, Stephan J. Sigrist et Tobias Eisenberg. « A pathological role of the Hsp40 protein Ydj1/DnaJA1 in models of Alzheimer’s disease ». Cell Stress 6, no 5 (9 mai 2022) : 61–64. http://dx.doi.org/10.15698/cst2022.05.267.
Texte intégralRésumé :
Alzheimer’s disease (AD) is the most common form of dementia with millions of people affected worldwide. Pathophysiological manifestations of AD include the extracellular accumulation of amyloid beta (Abeta) pep-tides, products of the proteolytic cleavage of the amy-loid precursor protein APP. Increasing evidence sug-gests that Abeta peptides also accumulate intracellular-ly, triggering neurotoxic events such as mitochondrial dysfunction. However, the molecular factors driving formation and toxicity of intracellular Abeta are poorly understood. In our recent study [EMBO Mol Med 2022 – e13952], we used different eukaryotic model systems to identify such factors. Based on a genetic screen in yeast and subsequent molecular analyses, we found that both the yeast chaperone Ydj1 and its human ortholog DnaJA1 physically interact with Abeta, facili-tate the aggregation of Abeta peptides into small oli-gomers and promote their translocation to mitochon-dria. Deletion or downregulation of this chaperone pro-tected from Abeta-mediated toxicity in yeast and Dro-sophila AD models, respectively. Most importantly, the identified chaperone is found to be dysregulated in post-mortem human samples of AD patients. Here, we aim to outline our key findings, highlighting pathological functions of a heat shock protein (Hsp) family member, which are generally considered protective rather than toxic during neurodegeneration. Our results thus chal-lenge the concept of developing generalized chaperone activation-based therapies and call for carefully consid-ering also maladaptive functions of specific heat shock proteins.
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Chalimoniuk, Małgorzata, Anna Stolecka, Magdalena Cakała, Susane Hauptmann, Kris Schulz, Uta Lipka, Kristine Leuner, Anne Eckert, Walter E. Muller et Joanna B. Strosznajder. « Amyloid beta enhances cytosolic phospholipase A2 level and arachidonic acid release via nitric oxide in APP-transfected PC12 cells. » Acta Biochimica Polonica 54, no 3 (23 août 2007) : 611–23. http://dx.doi.org/10.18388/abp.2007_3235.
Texte intégralRésumé :
Cytosolic phospholipase A2 (cPLA2) preferentially liberates arachidonic acid (AA), which is known to be elevated in Alzheimer's disease (AD). The aim of this study was to investigate the possible relationship between enhanced nitric oxide (NO) generation observed in AD and cPLA2 protein level, phosphorylation, and AA release in rat pheochromocytoma cell lines (PC12) differing in amyloid beta secretion. PC12 control cells, PC12 cells bearing the Swedish double mutation in amyloid beta precursor protein (APPsw), and PC12 cells transfected with human APP (APPwt) were used. The transfected APPwt and APPsw PC12 cells showed an about 2.8- and 4.8-fold increase of amyloid beta (Abeta) secretion comparing to control PC12 cells. An increase of NO synthase activity, cGMP and free radical levels in APPsw and APPwt PC12 cells was observed. cPLA2 protein level was higher in APPsw and APPwt PC12 cells comparing to PC12 cells. Moreover, phosphorylated cPLA2 protein level and [3H]AA release were also higher in APP-transfected PC12 cells than in the control PC12 cells. An NO donor, sodium nitroprusside, stimulated [3H]AA release from prelabeled cells. The highest NO-induced AA release was observed in control PC12 cells, the effect in the other cell lines being statistically insignificant. Inhibition of cPLA2 by AACOCF3 significantly decreased the AA release. Inhibitors of nNOS and gamma-secretase reduced AA release in APPsw and APPwt PC12 cells. The basal cytosolic [Ca2+](i) and mitochondrial Ca2+ concentration was not changed in all investigated cell lines. Stimulation with thapsigargin increased the cytosolic and mitochondrial Ca2+ level, activated NOS and stimulated AA release in APP-transfected PC12 cells. These results indicate that Abeta peptides enhance the protein level and phosphorylation of cPLA2 and AA release by the NO signaling pathway.
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Bathini, Praveen, Tao Sun, Mathias Schenk, Stephan Schilling, Nathan J. McDannold et Cynthia A. Lemere. « Acute Effects of Focused Ultrasound-Induced Blood-Brain Barrier Opening on Anti-Pyroglu3 Abeta Antibody Delivery and Immune Responses ». Biomolecules 12, no 7 (6 juillet 2022) : 951. http://dx.doi.org/10.3390/biom12070951.
Texte intégralRésumé :
Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS is limited due to the blood-brain-barrier (BBB). Focused ultrasound (FUS) is a method to induce a temporary opening of the BBB to enhance the delivery of therapeutic agents to the CNS. In this study, we evaluated the acute effects of FUS and whether the use of FUS-induced BBB opening enhances the delivery of 07/2a mAb, an anti-pyroglutamate-3 Aβ antibody, in aged 24 mo-old APP/PS1dE9 transgenic mice. FUS was performed either unilaterally or bilaterally with mAb infusion and the short-term effect was analyzed 4 h and 72 h post-treatment. Quantitative analysis by ELISA showed a 5–6-fold increase in 07/2a mAb levels in the brain at both time points and an increased brain-to-blood ratio of the antibody. Immunohistochemistry demonstrated an increase in IgG2a mAb detection particularly in the cortex, enhanced immunoreactivity of resident Iba1+ and phagocytic CD68+ microglial cells, and a transient increase in the infiltration of Ly6G+ immune cells. Cerebral microbleeds were not altered in the unilaterally or bilaterally sonicated hemispheres. Overall, this study shows the potential of FUS therapy for the enhanced delivery of CNS therapeutics.
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Juszczyk, Paulina, Aleksandra S. Kołodziejczyk et Zbigniew Grzonka. « Circular dichroism and aggregation studies of amyloid beta (11-8) fragment and its variants. » Acta Biochimica Polonica 52, no 2 (25 juin 2005) : 425–31. http://dx.doi.org/10.18388/abp.2005_3455.
Texte intégralRésumé :
Aggregation of Abeta peptides is a seminal event in Alzheimer's disease. Detailed understanding of Abeta assembly would facilitate the targeting and design of fibrillogenesis inhibitors. Here comparative conformational and aggregation studies using CD spectroscopy and thioflavine T fluorescence assay are presented. As a model peptide, the 11-28 fragment of Abeta was used. This model peptide is known to contain the core region responsible for Abeta aggregation. The structural and aggregational behaviour of the peptide was compared with the properties of its variants corresponding to natural, clinically relevant mutants at positions 21-23 (A21G, E22K, E22G, E22Q and D23N). In HFIP (hexafluoro-2-propanol), a strong alpha-helix inducer, the CD spectra revealed an unexpectedly high amount of beta-sheet conformation. The aggregation process of Abeta(11-28) variants provoked by water addition to HFIP was found to be consistent with a model of an alpha-helix-containing intermediate. The aggregation propensity of all Abeta(11-28) variants was also compared and discussed.
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Ramakrishna, Narayan, Marilyn Smedman et Bruce Gillam. « Suppression of Alzheimer Amyloid Precursor Protein (APP) Expression by Exogenous APP mRNA ». Archives of Biochemistry and Biophysics 326, no 2 (février 1996) : 243–51. http://dx.doi.org/10.1006/abbi.1996.0072.
Texte intégralThèses sur le sujet "AMYLOID, APP, ABETA, ALZHEIMER"
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CATANIA, MARCELLA. « Anti-amyloidogenicactivity of a mutant form of Aβ : a new strategy for Alzheimer therapy ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2012. http://hdl.handle.net/10281/29859.
Texte intégralRésumé :
Amyloid-β precursor protein (APP) mutations cause familial Alzheimer’s disease with virtually complete penetrance. We found an APP mutation (A673V) that causes disease only in the homozygous state, while heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced amyloid β (Aβ) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Aβ aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance, and have implications for genetic screening and the potential treatment of Alzheimer’s disease.
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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.
Texte intégralRésumé :
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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Ghenimi, Rahab Nadirah. « Action des rétinoïdes et processus neurodégénératifs associés à la maladie d'Alzheimer ». Thesis, Bordeaux 1, 2009. http://www.theses.fr/2009BOR13807/document.
Texte intégralRésumé :
Un ensemble des données cohérentes de la littérature plaide en faveur d'une relation entre une baisse d'activité de la voie de signalisation de la vitamine A, des altérations de la plasticité synaptique et des déficits mnésiques spécifiques associés au vieillissement. Une diminution de l'activité de cette voie de signalisation est également évoquée dans les processus neurodégénératifs caractéristiques de la maladie d'Alzheimer. Dans ce contexte, les objectifs de ce travail étaient de mieux comprendre les conséquences neuro-anatomiques et fonctionnelles d'une baisse d'activité de la voie de signalisation de la vitamine A. Notre approche expérimentale a mis en œuvre 2 modèles animaux, un modèle de carence vitaminique A qui induit spécifiquement une baisse d'activité de sa voie de signalisation et un modèle d'hypothyroïdie dont il a été montré qu'il induit aussi une hypoactivité de la voie de signalisation de la vitamine A. La démarche expérimentale conduite chez les rats carencés en vitamine A comporte deux volets : (i) un volet mettant en œuvre l’imagerie et la spectroscopie RMN, (ii) un volet moléculaire consacrée à l’étude de l’expression de gènes cibles des rétinoïdes impliqués dans le processus amyloïdogène. Les mesures ont été réalisées, d'une part, chez des animaux soumis à un régime dépourvu en vitamine A pendant 10 semaines et d'autre part, chez des animaux soumis à ce même régime pendant une durée de 13 ou 14 semaines. Une partie des animaux carencés a été traitée par de l'AR. Les résultats montrent que dès 10 semaines de carence, les animaux présentent une altération du métabolisme et de son action cellulaire de la vitamine A qui se traduit par (i) une diminution significative du taux de vitamine A sérique, (ii) une diminution du taux d'ARNm codant pour les récepteurs RAR, dans le cerveau entier, le striatum, l'hippocampe et de manière moins prononcée le cortex des animaux. Après 10 semaines de régime dépourvu en vitamine A, des modifications métaboliques ont été mises en évidence essentiellement dans le cortex. Elles se traduisent par une hausse du (i) NAA/Cr, marqueur de la densité neuronale corrigée par une administration d'AR, et (ii) du GSH/Cr, indicateur du potentiel antioxydant cellulaire dans cette structure. Au plan anatomique, un ralentissement de la croissance cérébrale a été observé dés la 7ème semaine de régime. Une diminution du volume hippocampique et une augmentation des espaces ventriculaires ont été observées à partir de 11 semaines de carence. Au plan moléculaire, aucune modification de l'expression du gène codant pour APP, ou du rapport APP770-751/APP695, considéré comme un indicateur précoce de la MA n'a été observée après 10 semaines de carence. Après 14 semaines de régime dépourvu en vitamine A, de profondes modifications métaboliques sont observées dans les trois structures à savoir le cortex, l’hippocampe et le striatum. Au plan moléculaire, les principaux résultats suggèrent un basculement du processus biochimique de dégradation de la protéine APP en faveur de la voie amyloïdogénique dans le cortex, et par voie de conséquence en faveur de la formation du peptide Aß. Cependant, aucune modification du taux protéique des peptides Aß n'a été mise en évidence dans le cortex et l'hippocampe des rats carencés. Le modèle d'hypothyroïdie que nous avons mis en oeuvre entraine bien une hypoactivité de la voie de signalisation de la T3, observée dans l'hippocampe des animaux et une diminution du taux d'ARNm codant pour RARß observée dans le cortex des rats hypothyroïdiens. Au plan moléculaire, l'augmentation du rapport APP770-751/APP695 a été observée chez les rats rendus hypothyroïdiens par rapport aux rats témoins. Comme chez les rats carencés en vitamine A, les indicateurs de la voie physiologique ne sont que très faiblement affectés chez les rats rendus hypothyroïdiensSome data reveal that retinoid hyposignalling, presumably resulting from decreased bioavailability of retinoid ligands naturally, was shown to result in aging-related synaptic plasticity and long term potentiation (LTP) alterations as well as in aging-related decline of cognitive function. Moreover, genetic, metabolic and dietary evidence has been provided for a defective retinoid metabolism in Alzheimer disease (AD). Thus, key steps of the amyloid production process are under the control of proteins whose expression is positively regulated by RA in vitro. In this context, the aims of this work were to better understand neuro-anatomical and functionnal consequences of retinoid signaling brain hypoactivity. Our experimental method uses two animal models: a Vitamin A deficiency model which induce especially an hypoactivity of retinoid pathway, and an hypothyroid model which was also characterized by an hypoactivity of retinoid pathway. In the fisrt model, two main approch were used : (i) an NMR imaging and spectroscopy approach, (ii) a molecular approach to study expression of retinoid target genes implicated in amyloidogenic process. NMR results showed that VAD induces severe anatomic and metabolic disorders in particular a slowing of brain growth, hippocampus atrophy, and a decrease of NAA/Cr, marker of neuronal density which was observed in cortex, hippocampus and striatum. Molecular results reveal a vitamin A deficiency-related dysregulation of the amyloid pathway in the cortex of rats, which is known to be the first brain area altered by AD development. In this area, 14 weeks of deprived diet induces physiological dysregulation in the modulation of RA target genes leading to an increased amount of ADAM10, BACE and PS1, with some modifications in amyloidogenic pathway but without increased amount of Aß peptides. In hypothyroid model, molecular results suggests that adult onset-hypothyroidism may induce the amyloidogenic pathway of APP processing by increasing activity of ß and ?secretases and levels of amyloid peptides mainly in hippocampus. Together these data argue for the idea that hypoactivity of retinoid signalling which occurs naturally with aging could be a factor participating in accelerating aging and that hypothyroidism that become more prevalent with advancing age, could increase, via a hyposignaling of T3 pathway, the vulnerability of amyloidogenic pathway of APP processing as well as of other clinical symptoms of AD
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Pavoni, Serena. « Mise au point d’un nouveau modèle d’organoïde cérébral humain pour l’étude des mécanismes d’interaction de la protéine prion et de l’amyloïde β ». Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS427.
Texte intégralRésumé :
Les mécanismes de type prion sont désormais reconnus comme sous-tendant la plupart des maladies neurodégénératives humaines, avec en premier lieu la maladie d’Alzheimer (MA) au niveau de ses 2 marqueurs spécifiques, l’amyloïde β (Aβ à l’origine de l’hypothèse étiopathogénique de la cascade amyloïde) et la protéine Tau phosphorylée. Par ailleurs la protéine du prion (PrPC) est décrite comme interagissant à de multiples niveaux avec le métabolisme de l’Aβ sans que les mécanismes physiopathologiques sous-jacents n’aient pu être expliqués. Pour sortir de l’impasse actuelle concernant le développement d’approches thérapeutiques efficaces pour la MA, l’industrie pharmaceutique a besoin de modèles expérimentaux innovants. En effet, à ce jour aucun modèle in vivo, en dépit des progrès réalisés avec les souris transgéniques, n’arrive à refléter la complexité cérébrale humaine ni à mimer une MA clinique. Les cultures in vitro en 2D sont quant à elles très éloignées des situations conduisant à l’accumulation d’agrégats protéiques pathologiques. Le but de notre thèse a été d’utiliser dans le domaine des neurosciences les nouvelles perspectives de recherche ouvertes par les technologies des cellules souches pluripotentes induites (cellules iPS) en développant un modèle de différentiation en 3D pour obtenir des organoïdes cérébraux humains (OC) (mini cerveaux). Leur capacité d’auto-organisation en 3D de tissu neuroectodermique nous a permis de recréer un système complexe mimant différentes structures cérébrales humaines dans lesquelles nous avons pu caractériser les marqueurs attendus. L’étude de l’expression des protéines d’intérêt APP et PrPC pendant la différentiation neurale a permis de caractériser la modulation des niveaux des deux protéines en fonction du temps de culture. Afin d’orienter le modèle vers des mécanismes d’accumulation protéique de type MA, nous avons testé différents inducteurs chimiques dont l’Aftin-5 qui est capable de moduler les voies post-traductionnelles de l’APP. Plusieurs stratégies de traitement ont été adoptées pour induire le clivage de l’APP et la génération d’Aβ. La production des fragments solubles Aβ38, Aβ40, Aβ42 a été mise en évidence par ELISA. Les niveaux générés sont reproductibles et l’augmentation du ratio Aβ42/Aβ40 est cohérente avec les données extrapolées des modèles murins et humains, ce qui a permis de valider notre modèle. Les niveaux d’expression génique et protéique de PrPC et de APP suite au traitement ont été analysés afin de mieux déterminer le rôle de l’interaction entre ces deux facteurs. L’objectif à long terme consiste à améliorer ce modèle, dont les limites actuelles sont notamment l’absence de vascularisation et le niveau de maturation du tissu neural. Le défi majeur dans le cadre de la culture des OC consiste donc à favoriser l’intégration du système vasculaire, et par ailleurs à accélérer le vieillissement in vitro pour l’étude de maladies neurodégénératives. La perspective de pouvoir automatiser le système de culture des OC permet d’envisager l’utilisation de ce modèle à plus grande échelle dans le cadre de test de cytotoxicité et/ou de criblage pharmacologique à haut débit pour identifier de nouvelles molécules thérapeutiques pour la MAPrion-like mechanisms are known to underlie most of human neurodegenerative diseases including Alzheimer’s disease (AD), which is characterized by two important pathological markers, β amyloid (or Aβ at the origin of the etiopathogenic amyloid cascade hypothesis) and phosphorylated tau protein. Furthermore, the prion protein (PrPC) interacts at multiple levels with the metabolism of Aβ, by mechanisms which are not well understood. To overcome the current limits in the development of efficient strategies to treat AD, the pharmaceutical industry requires innovative experimental models. However, even if a lot of progress has been achieved by using transgenic mouse models, to date no in vivo model can reflect the complexity of human brain or reproduce a clinical context. 2D in vitro cell culture models are unable to allow the aggregation and accumulation of pathological proteins as observed in vivo. The aim of this study consists in taking advantage of the research prospects offered by induced pluripotent stem cell (iPSCs) in the field of neurosciences. iPSCs can be used to generate 3D models of differentiation also called human cerebral organoids or mini-brains (MBs). Their ability to self-organise in 3D neuroectodermic tissue leds to a complex system that mimics different human cerebral structures in which we were able to characterize the expected markers. The study of the two proteins of interest (APP and PrPC) during neural differentiation has allowed us to follow the modulation of protein expression level occurring during the in vitro development of the human MBs. In order to use this model to reproduce the protein accumulation mechanisms seen in AD, we have tested chemical inductors such as Aftin-5 in order to modulate the APP post-transcriptional pathway towards a pathological outcome. Many strategies of treatment are adopted to lead APP cleavage and Aβ generation. The production of soluble fragments Aβ38, Aβ40, Aβ42 in the supernatant of organoids has been showed using ELISA technique. The levels generated are reproducible and the increase of Aβ42/Aβ40 ratio is consistent with extrapolated data from mouse and human models thus validating our model. Analysis at the gene and protein level has been assessed in order to understand the interaction between PrPC and APP after treatment. The long-term goal consists in improving this model which is notably hampered by the absence of vascularization and the low level of maturation of the neural tissue. The main challenge in MB culture thus consists in the integration of the vascular system, and also in increasing the speed of ageing process in vitro for the study of neurodegenerative diseases. In the long term, the prospect of automating the culture of MBs would allow the use of the system for cytotoxicity testing and/or high throughput screening for the discovery of new drugs for AD
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Karlnoski, Rachel Anne. « Optimization of anti-Abeta antibody therapy ». [Tampa, Fla.] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0002145.
Texte intégral
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Paz, Sandra Isabel Moreira Pinto Vieira Guerra e. « Phosphorylation-dependent Alzheimer's Amyloid precursor protein (APP) targeting ». Doctoral thesis, Universidade de Aveiro, 2006. http://hdl.handle.net/10773/4629.
Texte intégralRésumé :
Doutoramento em BiologiaA Doença de Alzheimer (DA) é uma das doenças neurodegenerativas mais comuns, e apresenta uma incidência mundial de 2-7% em indivíduos com mais de 65 anos e de cerca de 15% em indivíduos acima dos 85 anos de idade. Apesar da sua etiologia multifactorial, há uma correlação bem descrita entre esta patologia e um peptídeo neurotóxico denominado Abeta. Este peptídeo deriva fisiológica e proteoliticamente de uma glicoproteína transmembranar com características de receptor: a Proteína Percursora de Amilóide de Alzheimer (PPA). As possíveis funções fisiológicas da proteína PPA, o seu destino e vias de processamento celulares, conjuntamente com possíveis proteínas celulares que com ela interajam, são assim tópicos de interesse e objectos de investigação científica mundial. Neste contexto tem sido amplamente descrito o envolvimento do processo de fosforilação de proteínas, uma importante modificação pós-transducional que regula muitos e variados acontecimentos intracelulares, na regulação do processamento da PPA. Apesar do exposto, muito pouco é conhecido acerca da fosforilação directa da própria PPA. Esta proteína possui na sua estrutura primária sequências consenso para fosforilação, quer no seu ectodomínio quer no seu domínio intracelular, já descritas como sofrendo fosforilação “in vitro” e “in vivo”. O resíduo Serina 655 pertence a um motivo funcional da APP, 653YTSI656, que forma um sinal de internalização e/ou de “sorting” basolateral. Este domínio é também o local de ligação para a APPBP2, uma proteína que interage com os microtubulos da célula. Embora ainda mal elucidados, os mecanismos pelos quais a fosforilação proteica regula o processamento da PPA parecem incluir uma alteração no tráfego desta proteína, sugerindo que o domínio fosforilável 653YTSI656 desempenha um papel importante nesse processo. Esta dissertação visou assim contribuir para elucidar o papel da fosforilação directa da molécula de APP, mais especificamente no seu resíduo Serina 655, na regulação do direcionamento e tráfego subcelular da proteína, e nas suas possíveis clivagens proteolíticas. De forma a respondermos a essas questões desenvolvemos um modelo experimental para seguir o tráfego intracelular, que usa uma combinação de biologia molecular, técnicas de microscopia de epifluorescência e técnicas de cultura celular. Os resultados obtidos implicam este resíduo como um sinal de direcionamento subcelular da proteína APP, e revelam como o redireccionamento desta proteína por fosforilação favorece um tipo de processamento não amiloidogénico desta. Adicionalmente, a fosforilação do resíduo Serina 655 parece possuir um papel regulador da actividade da PPA como molécula de transdução de sinais. As implicações destas observações na DA e em novas aplicações terapêuticas para a doença são subsequentemente discutidas.
Alzheimer’s Disease (AD) is a common neurodegenerative disease affecting individuals worldwide with an incidence of 2-7% of post-65 and 15% of post-85 years old. This disease is multifactorial in its etiology but central to its pathology is a neurotoxic peptide termed Abeta. This peptide is physiologically derived by a proteolytic process on the transmembranar Alzheimer’s Amyloid Precursor Protein (APP). Protein phosphorylation-dependent APP processing has been widely described and although the mechanisms involved remain far from clarified, alterations in APP trafficking seem to occur as part of the answer. Furthermore, the occurrence of consensus phosphorylation sites in the APP intracellular domain has been known for long, but little was known regarding the direct phosphorylation of APP. Efforts in unravelling the role of these domains are finally being successful in placing them as key control points in APP targeting and processing. Among these consensus sequences, the less studied 653YTSI656 motif forms a characteristic internalisation and/or basolateral sorting signal sequence, and is known to be the binding site for a microtubuleinteracting protein (APPBP2). Phosphorylation of this motif was thus suggested to be involved in APP targeting regulation, hitherto all attempts failed to confirm it or even to reveal substantial evidences. In this project, the role of the 653YTSI656 idomain, and in particular the phosphorylatable serine 655, in APP trafficking and proteolytic processing was studied. In order to address this question a new experimental methodology was developed, which coupled molecular biology, fluorescence imaging, and cell culture techniques. APP point mutants, mimicking serine 655 phosphorylatedand dephosphorylated-status, and tagged with the green-fluorescent protein, were used to study protein trafficking dynamics and processing. Results obtained place serine 655 phosphorylation as a key signal in APP sorting and targeting to specific subcellular locations. Also of high relevance was the observed implication of serine 655 phosphorylation as a regulatory mechanism that maybe involved in controlling APP function as a signal transducer. The implications of these observations in AD pathogenesis and therapeutic approaches are discussed.
FCT - PRAXIS XXI/BD/16218/98
FCT - POCTI/BCI/34349/1999
Project DIADEM, QLK3-CT- 2001/02362
Fundação Calouste Gulbenkian
Fundação Astrazeneca
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Oskarsson, Marie. « Islet amyloid polypeptide (IAPP) in Type 2 diabetes and Alzheimer disease ». Doctoral thesis, Uppsala universitet, Institutionen för medicinsk cellbiologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-265501.
Texte intégralRésumé :
The misfolding and aggregation of the beta cell hormone islet amyloid polypeptide (IAPP) into amyloid fibrils is the main pathological finding in islets of Langerhans in type 2 diabetes. Pathological assemblies of IAPP are cytotoxic and believed to contribute to the loss of insulin-producing beta cells. Changes in the microenvironment that could trigger the aggregation of IAPP are largely unknown. So is the possibility that islet amyloid can spread within or between tissues. The present thesis have explored the roles of glycosaminoglycan heparan sulfate (HS) and the novel anti-amyloid chaperone Bri2 BRICHOS domain in the assembly of IAPP amyloid and cytotoxic IAPP aggregates. Furthermore, cross-seeding as a molecular interaction between the observed connection of type 2 diabetes and Alzheimer disease has been examined. The N-terminal region of IAPP was required for binding to HS structures and induction of binding promoted amyloid formation. Interference in the HS-IAPP interaction by heparanase degradation of HS or by introducing short, soluble HS-structure fragments reduced amyloid deposition in cultured islets. Cytotoxicity induced by extracellular, aggregating IAPP was mediated via interactions with cell-surface HS. This suggests that HS plays an important role in islet amyloid deposition and associated toxicity. BRICHOS domain containing protein Bri2 was highly expressed in human beta cells and colocalized with IAPP intracellularly and in islet amyloid deposits. The BRICHOS domain effectively attenuated both IAPP amyloid formation and IAPP-induced cytotoxicity. These results propose Bri2 BRICHOS as a novel chaperone preventing IAPP aggregation in beta cells. The intravenous injection of IAPP, proIAPP or amyloid-β (Aβ) fibrils enhanced islet amyloidosis in transgenic human IAPP mice, demonstrating that both homologous- and heterologous seeding of islet amyloid can occur in vivo. IAPP colocalized with Aβ in brain amyloid from AD patients, and AD patients diagnosed with T2D displayed increased proportions of neuritic plaques, the more pathogenic plaque subtype. In conclusion, both IAPP amyloid formation and the cytotoxic effects of IAPP is dependent on interactions with HS whereas interactions with Bri2 BRICHOS is protective. Cross-seeding between Aβ and IAPP can occur in vivo and the two peptides colocalize in brain amyloid in AD patients.
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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.
Texte intégralRésumé :
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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Rocha, Joana Fernandes da. « Characterizing Alzeimer's amyloid precursor protein (APP) neurotrophic functions ». Doctoral thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22225.
Texte intégralRésumé :
Doutoramento em BiomedicinaThe Amyloid Precursor Protein (APP) is a type 1 membrane glycoprotein, mainly known as the precursor of the amyloid β-peptide, a central player in Alzheimer’s disease. Nevertheless, APP has been established as a neuromodulator of developing and mature nervous system. Alterations in the level or activity of APP and APP fragments seem to play a critical role in several neurodegenerative and neurodevelopment disorders. APP is a complex molecule due to the intricate relationships between its intracellular trafficking, posttranslational modifications, proteolytic cleavages, and multiple protein interactors. Various studies currently address the physiological roles of APP and its fragments, but there are contradictory results and missing pieces that need further work. The main objective of this thesis was to contribute to the characterization of the role of APP in neuronal differentiation. Particularly, we focused on mechanisms mediated by APP, its fragment sAPP, and APP phosphorylation at serine 655. First, we characterized the APP protein in Retinoic Acid (RA)-induced SHSY5Y cell differentiation. The comprehensive analysis of this model exposed a biphasic temporal response: a first early phase (D0-D4), where a sAPP/APP peak assists the emergence of new processes and their elongation into neurites; and a second phase (D4-D8) when increased holoAPP protein levels are necessary to sustain neuritic elongation and stabilization. In line with our main aim, we subsequently characterized the relationship between APP and the neurotrophic EGF-EGFR-ERK signaling pathway. We showed, for the first time, that APP interacts with proEGF, and confirmed the interaction with EGFR. Furthermore, we showed that combined APP and EGF have a synergistic effect on neuronal-like differentiation, related to enhanced ERK1/2 activation, and observed that APP modulates EGFR expression levels and trafficking. Both ERK1/2 activation and EGFR seem to be modulated by the APP S655 phosphorylation state, and phosphorylation at this residue favours dendritogenesis in mice cortical neurons. Finally, we focused on discovering APP protein interactors dependent on S655 phosphorylation and with a role in neuronal differentiation. SH-SY5Y differentiated cells, overexpressing APPWt or S655 phosphomutants, were used to immunoprecipitate the specific APP proteins and their respective interacting partners, later identified by mass spectrometry. The dephosphoS655 APP interactome was enriched in functions associated with cytoskeleton organization, and these cells were particularly associated with actin remodeling. The phosphoS655 APP interactome included proteins involved in the regulation of survival and differentiation, and in various signaling pathways, correlating well with an enhanced neurite outgrowth displayed by these cells. We hope that the knowledge here gathered can contribute to a better comprehension of APP-driven neurotrophic roles and underlying mechanisms.
A Proteína Precursora de Amilóide (APP) é uma proteína membranar mais conhecida por ser precursora do péptido Amilóide β, tendo por isso um papel central na doença de Alzheimer. Não obstante, a APP tem sido reconhecida como neuromodulador do sistema nervoso central. Alterações nos níveis ou na atividade da APP e seus fragmentos estão implicadas em diferentes doenças neurológicas. As relações entre o seu transporte intracelular, modificações pós-traducionais, corte proteolítico, e proteínas com as quais interage são complexas e multifacetadas. Talvez por isso, estudos focados no papel fisiológico da APP apresentem resultados contraditórios e muitas questões em aberto. O objetivo deste trabalho consistiu na caracterização do papel fisiológico da APP na diferenciação neuronal. Particularmente, focámo-nos nos mecanismos mediados pela APP e fragmento sAPP, e a fosforilação da APP no resíduo serina 655. Inicialmente, caracterizámos a proteína APP ao longo da diferenciação de células SH-SY5Y com ácido retinóico (RA). A análise sistemática deste modelo permitiu delimitar uma resposta bifásica: na primeira fase (D0-D4), um pico de sAPP/APP acompanha o aparecimento de novos processos e o crescimento a neurites; na segunda fase (D4-D8) o aumento nos níveis da APP suporta o crescimento e manutenção das neurites. Caracterizámos posteriormente a relação entre a APP e a via de sinalização EGF-EGFR-ERK na diferenciação neuronal. Demonstrámos, pela primeira vez, que a APP interage com o proEGF, e confirmámos a sua ligação ao EGFR. Adicionalmente, observámos que a APP e o EGF têm um efeito sinérgico na diferenciação tipo-neuronal e aumento da ativação da ERK1/2, e que a APP afeta os níveis e transporte do EGFR. Estes mecanismos são modulados pela fosforilação da APP na S655, que favorece a dendritogénese em neurónios corticais de ratinho. Por último, focámo-nos na identificação de proteínas interatoras da APP dependentes da fosforilação em S655 e com função na diferenciação neuronal. Usando células SH-SY5Y diferenciadas e a sobrexpressar a APPWt ou fosfomutantes da S655, imunoprecipitámos as diferentes APPs e seus interatores, posteriormente identificados por espectrometria de massa. O interatoma da APP desfosforilada é enriquecido em funções associadas à organização do citoesqueleto, levando a uma maior reorganização da actina. O interatoma da APP fosforilada incluí proteínas envolvidas na regulação de sobrevivência e diferenciação, e em várias vias de sinalização, o que se correlaciona com o favorecimento de neurites nestas células. Com este trabalho esperamos ter contribuído para uma melhor compreensão do papel neurotrófico da APP e dos mecanismos subjacentes a este.
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Sahlin, Charlotte. « Pathogenic Mechanisms of the Arctic Alzheimer Mutation ». Doctoral thesis, Uppsala University, Department of Public Health and Caring Sciences, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7582.
Texte intégralRésumé :
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, neuropathologically characterized by neurofibrillay tangles and deposition of amyloid-β (Aβ) peptides. Several mutations in the gene for amyloid precursor protein (APP) cause familial AD and affect APP processing leading to increased levels of Aβ42. However, the Arctic Alzheimer mutation (APP E693G) reduces Aβ levels. Instead, the increased tendency of Arctic Aβ peptides to form Aβ protofibrils is thought to contribute to the pathogenesis.
In this thesis, the pathogenic mechanisms of the Arctic mutation were further investigated, specifically addressing if and how the mutation affects APP processing. Evidence of a shift towards β-secretase cleavage of Arctic APP was demonstrated. Arctic APP did not appear to be an inferior substrate for α-secretase, but the availability of Arctic APP for α-secretase cleavage was reduced, with diminished levels of cell surface APP in Arctic cells. Interestingly, administration of the fatty acid docosahexaenoic acid (DHA) stimulated α-secretase cleavage and partly reversed the effects of the Arctic mutation on APP processing.
In contrast to previous findings, the Arctic mutation generated enhanced total Aβ levels suggesting increased Aβ production. Importantly, this thesis illustrates and explains why measures of both Arctic and wild type Aβ levels are highly dependent upon the Aβ assay used, with enzyme-linked immunosorbent assay (ELISA) and Western blot generating different results. It was shown that these differences were due to inefficient detection of Aβ oligomers by ELISA leading to an underestimation of total Aβ levels.
In conclusion, the Arctic APP mutation leads to AD by multiple mechanisms. It facilitates protofibril formation, but it also alters trafficking and processing of APP which leads to increased steady state levels of total Aβ, in particular at intracellular locations. Importantly, these studies highlight mechanisms, other than enhanced production of Aβ peptide monomers, which could be implicated in sporadic AD.
Chapitres de livres sur le sujet "AMYLOID, APP, ABETA, ALZHEIMER"
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Gardella, J. E., J. Ghiso, G. A. Gorgone, D. Marratta, A. P. Kaplan, B. Frangione et P. D. Gorevic. « Immunoreactivity of Alzheimer Amyloid Precursor Protein (APP) Specific Antisera with Platelet Granule Constituents ». Dans Amyloid and Amyloidosis 1990, 722–25. Dordrecht : Springer Netherlands, 1991. http://dx.doi.org/10.1007/978-94-011-3284-8_177.
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Tanzi, Rudolph E. « From the amyloid β protein (A4) to isolation of the first Alzheimer’s disease gene : amyloid β (A4) precursor protein (APP) ». Dans Alzheimer : 100 Years and Beyond, 163–69. Berlin, Heidelberg : Springer Berlin Heidelberg, 2006. http://dx.doi.org/10.1007/978-3-540-37652-1_17.
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Schubert, Walter, Karin Agha-Amiri, Oleg Mayboroda et Christoph Rethfeldt. « Dipeptidyl Peptidase IV (CD26) and Alzheimer Amyloid Protein Precursor (APP) in Polymyositis ». Dans Advances in Experimental Medicine and Biology, 273–77. Boston, MA : Springer US, 1997. http://dx.doi.org/10.1007/978-1-4757-9613-1_36.
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« Taking Down the Unindicted Co-Conspirators of Amyloid β-Peptide-Mediated Neuronal Death : Shared Gene Regulation of BACE1 and APP Genes Interacting with CREB, Fe65 and YY1 Transcription Factors ». Dans Advances in Alzheimer Research, sous la direction de Debomoy K. Lahiri, Yuan-Wen Ge, Jack T. Rogers, Kumar Sambamurti, Nigel H. Greig et Bryan Maloney, 128–46. BENTHAM SCIENCE PUBLISHERS, 2013. http://dx.doi.org/10.2174/9781608054954113010009.
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Ahmed, Jessica. « Development of Specific Gamma Secretase Inhibitors ». Dans Handbook of Research on Systems Biology Applications in Medicine, 423–37. IGI Global, 2009. http://dx.doi.org/10.4018/978-1-60566-076-9.ch025.
Texte intégralRésumé :
Secretases are aspartic proteases, which specifically trim important, medically relevant targets such as the amyloid-precursor protein (APP) or the Notch-receptor. Therefore, changes in their activity can lead to dramatic diseases like M. Alzheimer caused by aggregation of peptidic fragments. On the other hand, the secretases are interesting targets for molecular therapy of the multiple myeloma, because the over-expressed Notch-receptor does not emerge into the native conformation until the cleavage by the presenilin, the active and catalytic subunit of the gamma secretase, occurs. Here, we focus on a novel methodology of structure-based drug development, feasible without prior knowledge of the target structure— analogy modeling. This combination of similarity screening, fold recognition, ligand-supported modeling, and docking is exemplarily illustrated for the structure of presenilin and specific inhibitors thereof.