Relevant bibliographies by topics / APP and amyloid fragments

Academic literature on the topic 'APP and amyloid fragments'

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Published: 8 June 2024

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  1. Journal articles
  2. Dissertations / Theses
  3. Books
  4. Book chapters
  5. Conference papers

Journal articles on the topic "APP and amyloid fragments":

1

Yokota, Masayuki, Takaomi C. Saido, Eiichi Tani, Ikuya Yamaura, and Nobutaka Minami. "Cytotoxic Fragment of Amyloid Precursor Protein Accumulates in Hippocampus after Global Forebrain Ischemia." Journal of Cerebral Blood Flow & Metabolism 16, no. 6 (November 1996): 1219–23. http://dx.doi.org/10.1097/00004647-199611000-00016.

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We developed an antibody specific to β-amyloid precursor protein (βAPP) fragments possessing the exact amino terminus of the β-amyloid peptide and examined its induction in postischemic hippocampus. In control hippocampus, this APP fragment was lightly observed in pyramidal neurons of CA sectors and dentate granule cells. Transient forebrain ischemia enhanced accumulation of the APP fragment in CA1 pyramidal neurons. Seven days after the ischemia, while the APP fragment was still observed in dentate granule cells and CA3 neurons, it disappeared in dead CA1 neurons. While astrocytes did not show in any immunoreactivity throughout the experiment, those in the CA1 sector showed moderate immunoreactivity 7 days after the ischemia. The APP fragment has a cytotoxic effect on cultured neurons. These results suggest that the accumulation of the cytotoxic APP fragment in CA1 neurons may play a role in the development of delayed neuronal death after the ischemic insult.
2

Chyung, Abraham S. C., Barry D. Greenberg, David G. Cook, Robert W. Doms, and Virginia M. Y. Lee. "Novel β-Secretase Cleavage of β-Amyloid Precursor Protein in the Endoplasmic Reticulum/Intermediate Compartment of NT2N Cells." Journal of Cell Biology 138, no. 3 (August 11, 1997): 671–80. http://dx.doi.org/10.1083/jcb.138.3.671.

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Previous studies have demonstrated that NT2N neurons derived from a human embryonal carcinoma cell line (NT2) constitutively process the endogenous wild-type β-amyloid precursor protein (APP) to amyloid β peptide in an intracellular compartment. These studies indicate that other proteolytic fragments generated by intracellular processing must also be present in these cells. Here we show that the NH2-terminal fragment of APP generated by β-secretase cleavage (APPβ) is indeed produced from the endogenous full length APP (APPFL). Pulse–chase studies demonstrated a precursor–product relationship between APPFL and APPβ as well as intracellular and secreted APPβ fragments. In addition, trypsin digestion of intact NT2N cells at 4°C did not abolish APPβ recovered from the cell lysates. Furthermore, the production of intracellular APPβ from wild-type APP appears to be a unique characteristic of postmitotic neurons, since intracellular APPβ was not detected in several non-neuronal cell lines. Significantly, production of APPβ occurred even when APP was retained in the ER/ intermediate compartment by inhibition with brefeldin A, incubation at 15°C, or by expression of exogenous APP bearing the dilysine ER retrieval motif.
3

Niederst, Emily D., Sol M. Reyna, and Lawrence S. B. Goldstein. "Axonal amyloid precursor protein and its fragments undergo somatodendritic endocytosis and processing." Molecular Biology of the Cell 26, no. 2 (January 15, 2015): 205–17. http://dx.doi.org/10.1091/mbc.e14-06-1049.

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Deposition of potentially neurotoxic Aβ fragments derived from amyloid precursor protein (APP) at synapses may be a key contributor to Alzheimer's disease. However, the location(s) of proteolytic processing and subsequent secretion of APP fragments from highly compartmentalized, euploid neurons that express APP and processing enzymes at normal levels is not well understood. To probe the behavior of endogenous APP, particularly in human neurons, we developed a system using neurons differentiated from human embryonic stem cells, cultured in microfluidic devices, to enable direct biochemical measurements from axons. Using human or mouse neurons in these devices, we measured levels of Aβ, sAPPα, and sAPPβ secreted solely from axons. We found that a majority of the fragments secreted from axons were processed in the soma, and many were dependent on somatic endocytosis for axonal secretion. We also observed that APP and the β-site APP cleaving enzyme were, for the most part, not dependent on endocytosis for axonal entry. These data establish that axonal entry and secretion of APP and its proteolytic processing products traverse different pathways in the somatodendritic compartment before axonal entry.
4

Lee, Ming-Sum, Shih-Chu Kao, Cynthia A. Lemere, Weiming Xia, Huang-Chun Tseng, Ying Zhou, Rachael Neve, Michael K. Ahlijanian, and Li-Huei Tsai. "APP processing is regulated by cytoplasmic phosphorylation." Journal of Cell Biology 163, no. 1 (October 13, 2003): 83–95. http://dx.doi.org/10.1083/jcb.200301115.

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Amyloid-β peptide (Aβ) aggregate in senile plaque is a key characteristic of Alzheimer's disease (AD). Here, we show that phosphorylation of amyloid precursor protein (APP) on threonine 668 (P-APP) may play a role in APP metabolism. In AD brains, P-APP accumulates in large vesicular structures in afflicted hippocampal pyramidal neurons that costain with antibodies against endosome markers and the β-secretase, BACE1. Western blot analysis reveals increased levels of T668-phosphorylated APP COOH-terminal fragments in hippocampal lysates from many AD but not control subjects. Importantly, P-APP cofractionates with endosome markers and BACE1 in an iodixanol gradient and displays extensive colocalization with BACE1 in rat primary cortical neurons. Furthermore, APP COOH-terminal fragments generated by BACE1 are preferentially phosphorylated on T668 verses those produced by α-secretase. The production of Aβ is significantly reduced when phosphorylation of T668 is either abolished by mutation or inhibited by T668 kinase inhibitors. Together, these results suggest that T668 phosphorylation may facilitate the BACE1 cleavage of APP to increase Aβ generation.
5

Feng, Fei, Yuanyuan Li, Nanqu Huang, and Yong Luo. "Icaritin, an inhibitor of beta-site amyloid cleaving enzyme-1, inhibits secretion of amyloid precursor protein in APP-PS1-HEK293 cells by impeding the amyloidogenic pathway." PeerJ 7 (December 10, 2019): e8219. http://dx.doi.org/10.7717/peerj.8219.

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Background Icaritin (ICT) is a prenylflavonoid derivative from Epimedium brevicornum Maxim. ICT has been shown to have neuroprotective effects. We investigate how ICT affects secretion of amyloid precursor protein (APP). Methods We exposed APP-PS1-HEK293 cells to ICT to investigate its effect on beta-site amyloid cleaving enzyme (BACE)1. Cell viability was evaluated by MTT and lactate dehydrogenase (LDH) assays. The half-maximal inhibitory concentration (IC50) of ICT for BACE1 was measured using fluorescence resonance energy transfer. Effects of ICT on the mRNA expression of APP were assessed by quantitative polymerase chain reaction, and protein expression was measured by western blotting and immunofluorescence. Results Icaritin inhibited BACE1 activity and IC50 was 5.70 ± 1.09 μM. Compared with the control group, at ICT concentrations of 5 μM and 10 μM, the viability increased and LDH leakage decreased in APP-PS1-293 cells. Also, mRNA expression of A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) increased, while that of BACE1 and presenilin-1 (PS1) decreased, upon ICT treatment. Western blotting and immunofluorescence confirmed that protein expression of ADAM10, BACE1 and PS1 showed the same trend. Expression of the APP fragments sAPPβ and C-terminal fragment β decreased, while that of sAPPα increased, upon ICT treatment. Expression of amyloid β peptides in APP-PS1-HEK293 cells was lower in ICT-treated groups compared with that in the control group. Conclusions Icaritin, as a BACE1 inhibitor, inhibits APP secretion in APP-PS1-HEK293 cells by impeding the amyloidogenic pathway.
6

Ghiso, J., A. Rostagno, J. E. Gardella, L. Liem, P. D. Gorevic, and B. Frangione. "A 109-amino-acid C-terminal fragment of Alzheimer's-disease amyloid precursor protein contains a sequence, -RHDS-, that promotes cell adhesion." Biochemical Journal 288, no. 3 (December 15, 1992): 1053–59. http://dx.doi.org/10.1042/bj2881053.

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Amyloid beta (A beta), the major constituent of the fibrils composing senile plaques and vascular amyloid deposits in Alzheimer's disease (AD) and related disorders, is a 39-42-residue self-aggregating degradation peptide of a larger multidomain membrane glycoprotein designated amyloid precursor protein (APP). An array of biological functions has been assigned to different APP domains, including growth regulation, neurotoxicity, inhibitory activity of serine proteinases and promotion of cell-cell and cell-matrix interactions. A beta is generated through an as-yet-unknown catabolic pathway that by-passes or inhibits the cleavage of APP within the A beta sequence. We have identified a 16 kDa intermediate APP C-terminal fragment containing A beta in leptomeningeal vessels of aged normal individuals and AD patients by means of its immunoreactivity with a panel of four different anti-(APP C-terminal) antibodies, indicating a different pathway of APP processing. Previous studies have indicated that the APP C-terminal domain is the most likely to be involved in cell-matrix interactions. A 109-amino-acid construct C109 with a sequence analogous to the C-terminal of APP (positions 587-695 of APP695), similar in length and immunoreactivity to the 16 kDa fragment, was found to promote cell adhesion. By use of synthetic peptides, this activity was initially located to the extracellular 28 residues of A beta. Inhibition studies demonstrated that the sequence RHDS (amino acids 5-8 of A beta, corresponding to residues 601-604 of APP695 was responsible for the adhesion-promoting activity. The interaction is dependent on bivalent cations and can be blocked either by the tetrapeptides RHDS and RGDS or by an anti-(beta 1 integrin) antibody. Thus, through integrin-like surface receptors, APP or its derivative proteolytic fragments containing the sequence RHDS may modulate cell-cell or cell-matrix interactions.
7

Cook, J. J., K. R. Wildsmith, D. B. Gilberto, M. A. Holahan, G. G. Kinney, P. D. Mathers, M. S. Michener, et al. "Acute -Secretase Inhibition of Nonhuman Primate CNS Shifts Amyloid Precursor Protein (APP) Metabolism from Amyloid- Production to Alternative APP Fragments without Amyloid- Rebound." Journal of Neuroscience 30, no. 19 (May 12, 2010): 6743–50. http://dx.doi.org/10.1523/jneurosci.1381-10.2010.

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8

Yu, Yang, Yang Gao, Bengt Winblad, Lars O. Tjernberg, and Sophia Schedin-Weiss. "A Super-Resolved View of the Alzheimer’s Disease-Related Amyloidogenic Pathway in Hippocampal Neurons." Journal of Alzheimer's Disease 83, no. 2 (September 14, 2021): 833–52. http://dx.doi.org/10.3233/jad-215008.

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Background: Processing of the amyloid-β protein precursor (AβPP) is neurophysiologically important due to the resulting fragments that regulate synapse biology, as well as potentially harmful due to generation of the 42 amino acid long amyloid β-peptide (Aβ42), which is a key player in Alzheimer’s disease. Objective: Our aim was to clarify the subcellular locations of the fragments involved in the amyloidogenic pathway in primary neurons with a focus on Aβ42 and its immediate substrate AβPP C-terminal fragment (APP-CTF). To overcome the difficulties of resolving these compartments due to their small size, we used super-resolution microscopy. Methods: Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional three-channel imaging, and quantitative image analyses. Results: The first (β-secretase) and second (γ-secretase) cleavages of AβPP were localized to functionally and distally distinct compartments. The β-secretase cleavage was observed in early endosomes in soma, where we were able to show that the liberated N- and C-terminal fragments were sorted into distinct vesicles budding from the early endosomes. Lack of colocalization of Aβ42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aβ42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AβPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aβ42 were localized in different compartments. Conclusion: These findings provide critical super-resolved insight into amyloidogenic AβPP processing in primary neurons.
9

Stieren, Emily S., Amina El Ayadi, Yao Xiao, Efraín Siller, Megan L. Landsverk, Andres F. Oberhauser, José M. Barral, and Darren Boehning. "Ubiquilin-1 Is a Molecular Chaperone for the Amyloid Precursor Protein." Journal of Biological Chemistry 286, no. 41 (August 18, 2011): 35689–98. http://dx.doi.org/10.1074/jbc.m111.243147.

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Alzheimer disease (AD) is associated with extracellular deposition of proteolytic fragments of amyloid precursor protein (APP). Although mutations in APP and proteases that mediate its processing are known to result in familial, early onset forms of AD, the mechanisms underlying the more common sporadic, yet genetically complex forms of the disease are still unclear. Four single-nucleotide polymorphisms within the ubiquilin-1 gene have been shown to be genetically associated with AD, implicating its gene product in the pathogenesis of late onset AD. However, genetic linkage between ubiquilin-1 and AD has not been confirmed in studies examining different populations. Here we show that regardless of genotype, ubiquilin-1 protein levels are significantly decreased in late onset AD patient brains, suggesting that diminished ubiquilin function may be a common denominator in AD progression. Our interrogation of putative ubiquilin-1 activities based on sequence similarities to proteins involved in cellular quality control showed that ubiquilin-1 can be biochemically defined as a bona fide molecular chaperone and that this activity is capable of preventing the aggregation of amyloid precursor protein both in vitro and in live neurons. Furthermore, we show that reduced activity of ubiquilin-1 results in augmented production of pathogenic amyloid precursor protein fragments as well as increased neuronal death. Our results support the notion that ubiquilin-1 chaperone activity is necessary to regulate the production of APP and its fragments and that diminished ubiquilin-1 levels may contribute to AD pathogenesis.
10

Ono, Kenji, Mikio Niwa, Hiromi Suzuki, Nahoko Bailey Kobayashi, Tetsuhiko Yoshida, and Makoto Sawada. "Signal Sequence-Dependent Orientation of Signal Peptide Fragments to Exosomes." International Journal of Molecular Sciences 23, no. 6 (March 15, 2022): 3137. http://dx.doi.org/10.3390/ijms23063137.

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Signal peptides (SPs) not only mediate targeting to the endoplasmic reticulum (ER) but also play important roles as biomarkers and substances with physiological activity in extracellular fluids including blood. SPs are thought to be degraded intracellularly, making it unclear how they are transported from the ER to the extracellular fluid. In a recent study, we showed that a C-terminal fragment of the SP of a type I membrane protein, amyloid precursor protein (APP), was secreted into the extracellular fluid via exosomes using transformed HEK293 cells expressing APP SP flanking a reporter protein. In the present study, we demonstrate that a N-terminal fragment of the SP from a type II membrane protein, human placental secreted alkaline phosphatase (SEAP), is contained in exosomes and secreted into the extracellular fluid using HEK-Blue hTLR3 cells, which express both a human toll-like receptor 3 gene and an inducible SEAP reporter gene. When HEK-Blue hTLR3 cells were stimulated with a TLR3 ligand, a N-terminal fragment of SEAP SP in exosomes was increased in parallel with SEAP secretion in a concentration-dependent manner. These results indicated that SP fragments are exosomal components. In addition, migrating SP fragments were determined by characteristics of the signal–anchor sequence of membrane proteins. Furthermore, we found that SP fragments could bind to calmodulin (CALM), which is a cytosolic protein and also a component of exosomes, suggesting its involvement in the transportation of SP fragments from the endoplasmic reticulum to exosomes.
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Journal articles Dissertations / Theses

Dissertations / Theses on the topic "APP and amyloid fragments":

1

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

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

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

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

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

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4

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

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

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Doutoramento em Biomedicina
The Amyloid Precursor Protein (APP) is a type 1 membrane glycoprotein, mainly known as the precursor of the amyloid β-peptide, a central player in Alzheimer’s disease. Nevertheless, APP has been established as a neuromodulator of developing and mature nervous system. Alterations in the level or activity of APP and APP fragments seem to play a critical role in several neurodegenerative and neurodevelopment disorders. APP is a complex molecule due to the intricate relationships between its intracellular trafficking, posttranslational modifications, proteolytic cleavages, and multiple protein interactors. Various studies currently address the physiological roles of APP and its fragments, but there are contradictory results and missing pieces that need further work. The main objective of this thesis was to contribute to the characterization of the role of APP in neuronal differentiation. Particularly, we focused on mechanisms mediated by APP, its fragment sAPP, and APP phosphorylation at serine 655. First, we characterized the APP protein in Retinoic Acid (RA)-induced SHSY5Y cell differentiation. The comprehensive analysis of this model exposed a biphasic temporal response: a first early phase (D0-D4), where a sAPP/APP peak assists the emergence of new processes and their elongation into neurites; and a second phase (D4-D8) when increased holoAPP protein levels are necessary to sustain neuritic elongation and stabilization. In line with our main aim, we subsequently characterized the relationship between APP and the neurotrophic EGF-EGFR-ERK signaling pathway. We showed, for the first time, that APP interacts with proEGF, and confirmed the interaction with EGFR. Furthermore, we showed that combined APP and EGF have a synergistic effect on neuronal-like differentiation, related to enhanced ERK1/2 activation, and observed that APP modulates EGFR expression levels and trafficking. Both ERK1/2 activation and EGFR seem to be modulated by the APP S655 phosphorylation state, and phosphorylation at this residue favours dendritogenesis in mice cortical neurons. Finally, we focused on discovering APP protein interactors dependent on S655 phosphorylation and with a role in neuronal differentiation. SH-SY5Y differentiated cells, overexpressing APPWt or S655 phosphomutants, were used to immunoprecipitate the specific APP proteins and their respective interacting partners, later identified by mass spectrometry. The dephosphoS655 APP interactome was enriched in functions associated with cytoskeleton organization, and these cells were particularly associated with actin remodeling. The phosphoS655 APP interactome included proteins involved in the regulation of survival and differentiation, and in various signaling pathways, correlating well with an enhanced neurite outgrowth displayed by these cells. We hope that the knowledge here gathered can contribute to a better comprehension of APP-driven neurotrophic roles and underlying mechanisms.
A Proteína Precursora de Amilóide (APP) é uma proteína membranar mais conhecida por ser precursora do péptido Amilóide β, tendo por isso um papel central na doença de Alzheimer. Não obstante, a APP tem sido reconhecida como neuromodulador do sistema nervoso central. Alterações nos níveis ou na atividade da APP e seus fragmentos estão implicadas em diferentes doenças neurológicas. As relações entre o seu transporte intracelular, modificações pós-traducionais, corte proteolítico, e proteínas com as quais interage são complexas e multifacetadas. Talvez por isso, estudos focados no papel fisiológico da APP apresentem resultados contraditórios e muitas questões em aberto. O objetivo deste trabalho consistiu na caracterização do papel fisiológico da APP na diferenciação neuronal. Particularmente, focámo-nos nos mecanismos mediados pela APP e fragmento sAPP, e a fosforilação da APP no resíduo serina 655. Inicialmente, caracterizámos a proteína APP ao longo da diferenciação de células SH-SY5Y com ácido retinóico (RA). A análise sistemática deste modelo permitiu delimitar uma resposta bifásica: na primeira fase (D0-D4), um pico de sAPP/APP acompanha o aparecimento de novos processos e o crescimento a neurites; na segunda fase (D4-D8) o aumento nos níveis da APP suporta o crescimento e manutenção das neurites. Caracterizámos posteriormente a relação entre a APP e a via de sinalização EGF-EGFR-ERK na diferenciação neuronal. Demonstrámos, pela primeira vez, que a APP interage com o proEGF, e confirmámos a sua ligação ao EGFR. Adicionalmente, observámos que a APP e o EGF têm um efeito sinérgico na diferenciação tipo-neuronal e aumento da ativação da ERK1/2, e que a APP afeta os níveis e transporte do EGFR. Estes mecanismos são modulados pela fosforilação da APP na S655, que favorece a dendritogénese em neurónios corticais de ratinho. Por último, focámo-nos na identificação de proteínas interatoras da APP dependentes da fosforilação em S655 e com função na diferenciação neuronal. Usando células SH-SY5Y diferenciadas e a sobrexpressar a APPWt ou fosfomutantes da S655, imunoprecipitámos as diferentes APPs e seus interatores, posteriormente identificados por espectrometria de massa. O interatoma da APP desfosforilada é enriquecido em funções associadas à organização do citoesqueleto, levando a uma maior reorganização da actina. O interatoma da APP fosforilada incluí proteínas envolvidas na regulação de sobrevivência e diferenciação, e em várias vias de sinalização, o que se correlaciona com o favorecimento de neurites nestas células. Com este trabalho esperamos ter contribuído para uma melhor compreensão do papel neurotrófico da APP e dos mecanismos subjacentes a este.
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Kim, Joung-Hun. "Electrophysiological and biochemical studies of #beta#-amyloid precursor protein fragments." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394383.

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Bark, Niklas. "Biophysical studies on aggregation processes and amyloid fibrils with focus on Alzheimer's disease /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-036-2/.

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

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

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

1

Sekoulidis, Joannis. Transgenic analysis of the Alzheimer's disease amyloid precursor protein (APP). 2004.

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Dooren, Tom V. Biochemical & Immuno-histochemical Analysis of App-processing & Amyloid Pathology in Single & Multiple Transgenic Mice As Models for Alzheimer's Disease. Leuven Univ Pr, 2006.

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Allen, Shelley J. Pathophysiology of Alzheimer’s disease. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780198779803.003.0002.

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We now know that the onset of the pathological processes leading to Alzheimer’s disease (AD) may be 15–20 years before symptoms appear. This focuses attention on synaptic changes and the early role of tau, and less on the hallmark amyloid plaques (Aβ‎) and neurofibrillary tau tangles. Sensitive biomarkers to allow early screening will be essential. Familial autosomal AD is the result of mutations in one of three genes (APP, PSEN1, or PSEN2), each directly related to increased Aβ‎, and informs pathological mechanisms in common sporadic cases, but are also subject to influence by many risk genes and environmental factors. The essential role of apolipoprotein E in neuronal repair and Aβ‎ clearance provides a therapeutic target but also a challenge in carriers of the risk gene APOE4. Current treatments are symptomatic, derived from neurotransmitter deficits seen; particularly cholinergic, but emerging data suggest alternative targets which may prove more productive.
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Wetzel, Ronald, and Rakesh Mishra. Structural Biology. Oxford University Press, 2014. http://dx.doi.org/10.1093/med/9780199929146.003.0012.

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The 3,144–amino acid huntingtin protein (HTT) folds in water into a structure consisting of compact, organized domains interspersed with intrinsically disordered protein (IDP) elements. The IDPs function as sites of post-translational modifications and proteolysis as well as in targeting, binding, and aggregation. Although the dominant structural motif of HTT is the α‎-helix–rich HEAT repeat, the expanded polyglutamine (polyQ) toxicity responsible for Huntington’s disease is most likely played out within intrinsically disordered HTT exon 1–like fragments consisting of the 16– to 17–amino acid N-terminal HTTNT segment, the polyQ segment, and a proline-rich segment. The physical behavior of HTT exon 1 fragments is dominated by interactive, polyQ repeat length–dependent structural transitions responsible for membrane and protein–protein interactions and the formation of tetramers, higher oligomers, amyloid fibrils, and inclusions. Understanding the basis of this solution behavior may be the key to disease mechanisms and molecular therapeutic strategies.

Book chapters on the topic "APP and amyloid fragments":

1

Suh, Yoo-Hun, Ji-Heui Seo, Yanji Xu, Chaejeong Heo, Najung Kim, Jun Ho Choi, Se Hoon Choi, Jong-Cheol Rah, Keun-A. Chang, and Won-Hyuk Suh. "Toxicity of App Fragments." In Mapping the Progress of Alzheimer’s and Parkinson’s Disease, 19–25. Boston, MA: Springer US, 2002. http://dx.doi.org/10.1007/978-0-306-47593-1_4.

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Esposito, Luke A. "Measuring APP Carboxy-Terminal Fragments." In Methods in Molecular Biology, 71–84. Totowa, NJ: Humana Press, 2010. http://dx.doi.org/10.1007/978-1-60761-744-0_6.

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Sisodia, S. S., H. H. Slunt, C. Van Koch, A. C. Y. Lo, and G. Thinakaran. "Studies of APP Biology: Analysis of APP Secretion and Characterization of an APP Homologue, APLP2." In Amyloid Protein Precursor in Development, Aging and Alzheimer’s Disease, 121–33. Berlin, Heidelberg: Springer Berlin Heidelberg, 1994. http://dx.doi.org/10.1007/978-3-662-01135-5_11.

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Gardella, J. E., J. Ghiso, G. A. Gorgone, D. Marratta, A. P. Kaplan, B. Frangione, and P. D. Gorevic. "Immunoreactivity of Alzheimer Amyloid Precursor Protein (APP) Specific Antisera with Platelet Granule Constituents." In 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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Gustavsson, Å., U. Engström, and P. Westermark. "Formation of Fibrils by Normal Transthyretin and Synthetic Transthyretin Fragments In Vitro." In Amyloid and Amyloidosis 1990, 591–94. Dordrecht: Springer Netherlands, 1991. http://dx.doi.org/10.1007/978-94-011-3284-8_145.

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Multhaup, G. "Studies of the Amyloid Precursor Protein (APP) in Brain: Regulation of APP-Ligand Binding." In Amyloid Protein Precursor in Development, Aging and Alzheimer’s Disease, 76–89. Berlin, Heidelberg: Springer Berlin Heidelberg, 1994. http://dx.doi.org/10.1007/978-3-662-01135-5_8.

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Linke, R. P., J. Floege, F. Lottspeich, and R. Deutzmann. "Several β2-Microglobulin Fragments Identified in an Amyloidoma in a Patient with Long-Term Hemodialysis." In Amyloid and Amyloidosis 1990, 369–72. Dordrecht: Springer Netherlands, 1991. http://dx.doi.org/10.1007/978-94-011-3284-8_93.

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Marks, N., and M. J. Berg. "Secretase Processing of Amyloid Precursor Protein (APP) and Neurodegeneration." In Handbook of Neurochemistry and Molecular Neurobiology, 469–514. Boston, MA: Springer US, 2007. http://dx.doi.org/10.1007/978-0-387-30379-6_16.

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Laczkó, I., S. Holly, Z. Kónya, J. Varga, K. Soós, M. Hollósi, and B. Penke. "Synthesis and structure investigation of amyloid small peptide fragments." In Peptides 1994, 549–50. Dordrecht: Springer Netherlands, 1995. http://dx.doi.org/10.1007/978-94-011-1468-4_249.

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Tobiassen, R., Å. Gustafsson, K. Sletten, B. Johansson, and P. Westermark. "Structural Studies of Transthyretin and Related Fragments Obtained from a Swedish Patient (V-ÅS 280) with Senile Systemic Amylodosis." In Amyloid and Amyloidosis 1990, 631–34. Dordrecht: Springer Netherlands, 1991. http://dx.doi.org/10.1007/978-94-011-3284-8_155.

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Conference papers on the topic "APP and amyloid fragments":

1

Frankiewicz, Lukasz P., Wiktor Banachewicz, and Aleksandra Misicka. "Aggregation studies of β-amyloid and prion protein fragments." In IXth Conference Biologically Active Peptides. Prague: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 2005. http://dx.doi.org/10.1135/css200508023.

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Shutikov, A. A., G. M. Arzumanyan, K. Z. Mamatkulov, E. Arynbek, and D. S. Zakrytnaya. "ANALYSIS OF THE SECONDARY STRUCTURE OF AΒ (1-42) PEPTIDE IN THE AMIDE I REGION BY RAMAN SPECTROSCOPY." In X Международная конференция молодых ученых: биоинформатиков, биотехнологов, биофизиков, вирусологов и молекулярных биологов — 2023. Novosibirsk State University, 2023. http://dx.doi.org/10.25205/978-5-4437-1526-1-220.

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Amyloid fibrils found in plaques in Alzheimer’s disease (AD) brains are composed of amyloid-β peptides. Aβ peptides are formed from the transmembrane amyloid precursor protein (APP). They have pronounced fibrillogenic properties, and its oligomers are toxic to nerve cells, causing their degeneration and death. Oligomeric amyloid-β (1-42) is thought to play a critical role in neurodegeneration in AD. In this work, we analyzed the conformational transformation of Aβ (1-42) peptides embedded in membrane mimetics by Raman spectroscopy. The main goal of the scientific study was to investigate the structural changes of the peptide leading to the formation of amyloid oligomers and fibrils.
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Theobald, Robert, and Henry Han. "Memantine Effects on Amyloid Plaque Load and Cognition in APP/SP1 Transgenic Mice." In ASPET 2024 Annual Meeting Abstract. American Society for Pharmacology and Experimental Therapeutics, 2024. http://dx.doi.org/10.1124/jpet.117.916790.

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Soares, Carolina, Débora G. Souza, Andreia Silva da Rocha, Luiza Machado, Bruna Bellaver, and Eduardo R. Zimmer. "BRAIN ENERGETICS EVALUATION IN EARLY STAGES OF AMYLOID PATHOLOGY IN A RAT MODEL OF ALZHEIMER’S DISEASE." In XIII Meeting of Researchers on Alzheimer's Disease and Related Disorders. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1980-5764.rpda086.

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Background: Transgenic models of Alzheimer’s disease (AD) overexpress human APP, PS1 or PS2 mutations. These models present amyloid-beta pathology but do not recapitulate the complexity of AD. Interestingly, the transgenic rat model TgF344-AD, which overpresses human APP and PS1 mutations, seems to follow a more similar disease progression, manifesting progressive tau tangle-like pathology and late cognitive impairment. Yet, whether they develop energy metabolism changes as we see in AD remains unclear. Objective: Here, we investigated brain bioenergetics in 6-7 months F344-AD/WT rats, an age where animals present early amyloid pathology but no memory impairment - mimicking the human preclinical AD. Methods: We used high-resolution respirometry to assess mitochondrial oxidative phosphorylation capacity (OXPHOS), electron transfer capacity (ET), respiratory control ratio (RCR) and reserve capacity (R) in brain homogenates of male and female F344-AD and WT rats (n = 6-8, per group). Results: The results were analyzed by Welch’s t test: 1. Frontal cortex a)OXPHOS (p=0.307); b)ET (p=0.99); c)RCR (p=0.138); d)R (p=0.482). 2. Hippocampus a)OXPHOS (p=0.446); b)ET (p=0.409); c)RCR (p=0.952); d)R (p=0.503). Conclusion: In conclusion, at 6-7 months, changes in the respirometry in the brain of F344-AD rats were not observed. We hypothesize that these measures will be altered at older ages.
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Gerstenmayer, Matthieu, Erwan Selingue, Francoise Geffroy, Sebastien Meriaux, and Benoit Larrat. "Notice of Removal: Weekly ultrasound induced blood-brain barrier openings seem to restore memory in APP/PS1dE9 amyloid mice model." In 2017 IEEE International Ultrasonics Symposium (IUS). IEEE, 2017. http://dx.doi.org/10.1109/ultsym.2017.8092315.

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Sobol, Anna, Paola Galluzzo, Shuang Liang, Brittany Rambo, Sylvia Skucha, Megan Weber, and Maurizio Bocchetta. "Abstract C40: Amyloid precursor protein (APP) synchronizes cell cycle progression and the rate of global protein synthesis in dividing cells." In Abstracts: Third AACR International Conference on Frontiers in Basic Cancer Research - September 18-22, 2013; National Harbor, MD. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.fbcr13-c40.

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Shakila, G., C. Meganathan, N. Sundaraganesan, and H. Saleem. "Pharmacophore based virtual screening, molecular docking and density functional theory approaches to discover the potent beta-amyloid precursor protein (B-APP) inhibitor." In 7TH NATIONAL CONFERENCE ON HIERARCHICALLY STRUCTURED MATERIALS (NCHSM-2019). AIP Publishing, 2019. http://dx.doi.org/10.1063/1.5114592.

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Jimenez, Stephannie, Gordana Rakic, Silvia Takahashi, and Nicolás Cardozo. "Cross-language Clone Detection for Mobile Apps." In Congresso Ibero-Americano em Engenharia de Software. Sociedade Brasileira de Computação, 2023. http://dx.doi.org/10.5753/cibse.2023.24696.

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Abstract:
Clone detection provides insight about replicated fragments in a code base. With the rise of multi-language code bases, new techniques addressing cross-language code clone detection enable the analysis of polyglot systems. Such techniques have not yet been applied to the mobile apps’ domain, which are naturally polyglot. Native mobile app developers must synchronize their code base in at least two different programming languages. App synchronization is a difficult and time-consuming maintenance task, as features can rapidly diverge between platforms, and feature identification must be performed manually. Our goal is to provide an analysis framework to reduce the impact of app synchronization. A first step in this direction consists on a structural algorithm for cross-language clone detection exploiting the idea behind enriched concrete syntax trees. Such trees are used as a common intermediate representation built from programming languages’ grammars, to detect similarities between app code bases. Our technique finds code similarities with 79% precision for controlled tests where Type 1-3 clones are manually injected for the analysis of both single- and cross-language cases for Kotlin and Dart. We evaluate our tool on a corpus of 52 mobile apps identifying code similarities with a precision of 65% to 84% for the full application logic.
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Rocha, Andreia, Bruna Bellaver, Luiza Machado, Carolina Soares, Pâmela C. L. Ferreira, Samuel Greggio Gianina T. Venturin, Jaderson C. da Costa, Diogo O. Souza, and Eduardo R. Zimmer. "TEMPORAL CHANGES IN ASTROCYTES ON A TRANSGENIC RAT MODEL OF AD." In XIII Meeting of Researchers on Alzheimer's Disease and Related Disorders. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1980-5764.rpda023.

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Abstract:
Background: Recent evidences have pointed to astrocytes as important players in the Alzheimer’s Disease (AD) pathogenesis. Objective: With this in mind, we aim to longitudinally investigate astrocyte changes in a new important AD transgenic model, the TgF344-AD rat, the first animal model harboring human APP/PS1 mutations which presents age-dependent amyloid and tau pathology. Methods: TgF344-AD rats and wild type littermates were evaluated in three time points: 3, 6 and 9 months of age. Rats underwent a [18F]FDG-microPET, a spatial-memory, an astrocytes CSF biomarkers (ELISA multiplex) and a glutamate uptake (ex-vivo slices) analysis. Examination of further time-points are being conducted at the moment. Results: At 9 months of age, TgF344-AD animals presented an increase in the cortical [18F]FDG uptake and a decline in their alternance performance in the Y-maze task. In the CSF analysis, GFAP was elevated at both 6 months and 9 months, while S100B presented a decrease at 6mo. Additionally, the cortical glutamate uptake was increased at 9 months. Conclusion: This study is the first to longitudinally investigate the in vivo brain glucose metabolism in the TgF344-AD rat model. Our results suggest that this model presents an early increase on glucose metabolism which may be related to astrocytes activation and the increase of glutamate uptake by these cells. Furthermore, we also identified a spatial memory impairment at the same age.

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