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Статті в журналах з теми "APP-CTFs":

1

Vaillant-Beuchot, Loan, Arnaud Mary, Raphaëlle Pardossi-Piquard, Alexandre Bourgeois, Inger Lauritzen, Fanny Eysert, Paula Fernanda Kinoshita, et al. "Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains." Acta Neuropathologica 141, no. 1 (October 20, 2020): 39–65. http://dx.doi.org/10.1007/s00401-020-02234-7.

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AbstractSeveral lines of recent evidence indicate that the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) could correspond to an etiological trigger of Alzheimer’s disease (AD) pathology. Altered mitochondrial homeostasis is considered an early event in AD development. However, the specific contribution of APP-CTFs to mitochondrial structure, function, and mitophagy defects remains to be established. Here, we demonstrate in neuroblastoma SH-SY5Y cells expressing either APP Swedish mutations, or the β-secretase-derived APP-CTF fragment (C99) combined with β- and γ-secretase inhibition, that APP-CTFs accumulation independently of Aβ triggers excessive mitochondrial morphology alteration (i.e., size alteration and cristae disorganization) associated with enhanced mitochondrial reactive oxygen species production. APP-CTFs accumulation also elicit basal mitophagy failure illustrated by enhanced conversion of LC3, accumulation of LC3-I and/or LC3-II, non-degradation of SQSTM1/p62, inconsistent Parkin and PINK1 recruitment to mitochondria, enhanced levels of membrane and matrix mitochondrial proteins, and deficient fusion of mitochondria with lysosomes. We confirm the contribution of APP-CTFs accumulation to morphological mitochondria alteration and impaired basal mitophagy in vivo in young 3xTgAD transgenic mice treated with γ-secretase inhibitor as well as in adeno-associated-virus-C99 injected mice. Comparison of aged 2xTgAD and 3xTgAD mice indicates that, besides APP-CTFs, an additional contribution of Aβ to late-stage mitophagy activation occurs. Importantly, we report on mitochondrial accumulation of APP-CTFs in human post-mortem sporadic AD brains correlating with mitophagy failure molecular signature. Since defective mitochondria homeostasis plays a pivotal role in AD pathogenesis, targeting mitochondrial dysfunctions and/or mitophagy by counteracting early APP-CTFs accumulation may represent relevant therapeutic interventions in AD.
2

Marttinen, Mikael, Catarina B. Ferreira, Kaisa M. A. Paldanius, Mari Takalo, Teemu Natunen, Petra Mäkinen, Luukas Leppänen та ін. "Presynaptic Vesicle Protein SEPTIN5 Regulates the Degradation of APP C-Terminal Fragments and the Levels of Aβ". Cells 9, № 11 (15 листопада 2020): 2482. http://dx.doi.org/10.3390/cells9112482.

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Alzheimer’s disease (AD) is a neurodegenerative disease characterized by aberrant amyloid-β (Aβ) and hyperphosphorylated tau aggregation. We have previously investigated the involvement of SEPTIN family members in AD-related cellular processes and discovered a role for SEPTIN8 in the sorting and accumulation of β-secretase. Here, we elucidated the potential role of SEPTIN5, an interaction partner of SEPTIN8, in the cellular processes relevant for AD, including amyloid precursor protein (APP) processing and the generation of Aβ. The in vitro and in vivo studies both revealed that the downregulation of SEPTIN5 reduced the levels of APP C-terminal fragments (APP CTFs) and Aβ in neuronal cells and in the cortex of Septin5 knockout mice. Mechanistic elucidation revealed that the downregulation of SEPTIN5 increased the degradation of APP CTFs, without affecting the secretory pathway-related trafficking or the endocytosis of APP. Furthermore, we found that the APP CTFs were degraded, to a large extent, via the autophagosomal pathway and that the downregulation of SEPTIN5 enhanced autophagosomal activity in neuronal cells as indicated by altered levels of key autophagosomal markers. Collectively, our data suggest that the downregulation of SEPTIN5 increases the autophagy-mediated degradation of APP CTFs, leading to reduced levels of Aβ in neuronal cells.
3

Hao, Candy Yan, Michael S. Perkinton, William Wai-Lun Chan, Ho Yin Edwin Chan, Christopher C. J. Miller, and Kwok-Fai Lau. "GULP1 is a novel APP-interacting protein that alters APP processing." Biochemical Journal 436, no. 3 (May 27, 2011): 631–39. http://dx.doi.org/10.1042/bj20110145.

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Altered production of Aβ (amyloid-β peptide), derived from the proteolytic cleavage of APP (amyloid precursor protein), is believed to be central to the pathogenesis of AD (Alzheimer's disease). Accumulating evidence reveals that APPc (APP C-terminal domain)-interacting proteins can influence APP processing. There is also evidence to suggest that APPc-interacting proteins work co-operatively and competitively to maintain normal APP functions and processing. Hence, identification of the full complement of APPc-interacting proteins is an important step for improving our understanding of APP processing. Using the yeast two-hybrid system, in the present study we identified GULP1 (engulfment adaptor protein 1) as a novel APPc-interacting protein. We found that the GULP1–APP interaction is mediated by the NPTY motif of APP and the GULP1 PTB (phosphotyrosine-binding) domain. Confocal microscopy revealed that a proportion of APP and GULP1 co-localized in neurons. In an APP–GAL4 reporter assay, we demonstrated that GULP1 altered the processing of APP. Moreover, overexpression of GULP1 enhanced the generation of APP CTFs (C-terminal fragments) and Aβ, whereas knockdown of GULP1 suppressed APP CTFs and Aβ production. The results of the present study reveal that GULP1 is a novel APP/APPc-interacting protein that influences APP processing and Aβ production.
4

Sivanesan, Senthilkumar, Ravi Mundugaru, and Jayakumar Rajadas. "Possible Clues for Brain Energy Translation via Endolysosomal Trafficking of APP-CTFs in Alzheimer’s Disease." Oxidative Medicine and Cellular Longevity 2018 (October 21, 2018): 1–11. http://dx.doi.org/10.1155/2018/2764831.

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Vascular dysfunctions, hypometabolism, and insulin resistance are high and early risk factors for Alzheimer’s disease (AD), a leading neurological disease associated with memory decline and cognitive dysfunctions. Early defects in glucose transporters and glycolysis occur during the course of AD progression. Hypometabolism begins well before the onset of early AD symptoms; this timing implicates the vulnerability of hypometabolic brain regions to beta-secretase 1 (BACE-1) upregulation, oxidative stress, inflammation, synaptic failure, and cell death. Despite the fact that ketone bodies, astrocyte-neuron lactate shuttle, pentose phosphate pathway (PPP), and glycogenolysis compensate to provide energy to the starving AD brain, a considerable energy crisis still persists and increases during disease progression. Studies that track brain energy metabolism in humans, animal models of AD, and in vitro studies reveal striking upregulation of beta-amyloid precursor protein (β-APP) and carboxy-terminal fragments (CTFs). Currently, the precise role of CTFs is unclear, but evidence supports increased endosomal-lysosomal trafficking of β-APP and CTFs through autophagy through a vague mechanism. While intracellular accumulation of Aβ is attributed as both the cause and consequence of a defective endolysosomal-autophagic system, much remains to be explored about the other β-APP cleavage products. Many recent works report altered amino acid catabolism and expression of several urea cycle enzymes in AD brains, but the precise cause for this dysregulation is not fully explained. In this paper, we try to connect the role of CTFs in the energy translation process in AD brain based on recent findings.
5

Lauritzen, I., R. Pardossi-Piquard, A. Bourgeois, A. Bécot, and F. Checler. "Does Intraneuronal Accumulation of Carboxyl-terminal Fragments of the Amyloid Precursor Protein Trigger Early Neurotoxicity in Alzheimer’s Disease?" Current Alzheimer Research 16, no. 5 (May 21, 2019): 453–57. http://dx.doi.org/10.2174/1567205016666190325092841.

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Background: Alzheimer’s disease (AD) is associated with extracellular accumulation and aggregation of amyloid β (Aβ) peptides ultimately seeding in senile plaques. Recent data show that their direct precursor C99 (βCTF) also accumulates in AD-affected brain as well as in AD-like mouse models. C99 is consistently detected much earlier than Aβ, suggesting that this metabolite could be an early contributor to AD pathology. C99 accumulates principally within endolysosomal and autophagic structures and its accumulation was described as both a consequence and one of the causes of endolysosomalautophagic pathology, the occurrence of which has been documented as an early defect in AD. C99 was also accompanied by C99-derived C83 (αCTF) accumulation occurring within the same intracellular organelles. Both these CTFs were found to dimerize leading to the generation of higher molecular weight CTFs, which were immunohistochemically characterized in situ by means of aggregate-specific antibodies. Discussion: Here, we discuss studies demonstrating a direct link between the accumulation of C99 and C99-derived APP-CTFs and early neurotoxicity. We discuss the role of C99 in endosomal-lysosomalautophagic dysfunction, neuroinflammation, early brain network alterations and synaptic dysfunction as well as in memory-related behavioral alterations, in triple transgenic mice as well as in newly developed AD animal models. Conclusion: This review summarizes current evidence suggesting a potential role of the β -secretasederived APP C-terminal fragment C99 in Alzheimer’s disease etiology
6

Wang, Bo-Jeng, Guor Mour Her, Ming-Kuan Hu, Yun-Wen Chen, Ying-Tsen Tung, Pei-Yi Wu, Wen-Ming Hsu, et al. "ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease." Proceedings of the National Academy of Sciences 114, no. 15 (March 28, 2017): E3129—E3138. http://dx.doi.org/10.1073/pnas.1618804114.

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Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer’s disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]- and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34–Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL-387,785 decreased the levels of C99 and secreted amyloid-β in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD.
7

Shinohara, Mitsuru, Naoyuki Sato, Hitomi Kurinami, Daisuke Takeuchi, Shuko Takeda, Motoko Noma, Hiromi Rakugi та Ryuichi Morishita. "Fluvastatin reduces Aβ levels in brain by upregulating APP-CTFs degradation and Aβ clearance". Neuroscience Research 65 (січень 2009): S64. http://dx.doi.org/10.1016/j.neures.2009.09.194.

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8

Xie, Zhongcong, Yuanlin Dong, Uta Maeda, Weiming Xia та Rudolph E. Tanzi. "RNA Interference Silencing of the Adaptor Molecules ShcC and Fe65 Differentially Affect Amyloid Precursor Protein Processing and Aβ Generation". Journal of Biological Chemistry 282, № 7 (14 грудня 2006): 4318–25. http://dx.doi.org/10.1074/jbc.m609293200.

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The amyloid precursor protein (APP) and its pathogenic by-product amyloid-β protein (Aβ) play central roles in Alzheimer disease (AD) neuropathogenesis. APP can be cleaved by β-secretase (BACE) and α-secretase to produce APP-C99 and APP-C83. These C-terminal fragments can then be cleaved by γ-secretase to produce Aβ and p3, respectively. p3 has been reported to promote apoptosis, and Aβ is the key component of senile plaques in AD brain. APP adaptor proteins with phosphotyrosine-binding domains, including ShcA (SHC1), ShcC (SHC3), and Fe65 (APBB1), can bind to and interact with the conserved YENPTY motif in the APP-C terminus. Here we have described for the first time the effects of RNA interference (RNAi) silencing of ShcA, ShcC, and Fe65 expression on APP processing and Aβ production. RNAi silencing of ShcC led to reductions in the levels of APP-C-terminal fragments (APP-CTFs) and Aβ in H4 human neuroglioma cells stably overexpressing full-length APP (H4-FL-APP cells) but not in those expressing APP-C99 (H4-APP-C99 cells). RNAi silencing of ShcC also led to reductions in BACE levels in H4-FL-APP cells. In contrast, RNAi silencing of the homologue ShcA had no effect on APP processing or Aβ levels. RNAi silencing of Fe65 increased APP-CTF levels, although also decreasing Aβ levels in H4-FL-APP cells. These findings suggest that pharmacologically blocking interaction of APP with ShcC and Fe65 may provide novel therapeutic strategies against AD.
9

Yang, Chuanbin, Cui-Zan Cai, Ju-Xian Song, Jie-Qiong Tan, Siva Sundara Kumar Durairajan, Ashok Iyaswamy, Ming-Yue Wu, et al. "NRBF2 is involved in the autophagic degradation process of APP-CTFs in Alzheimer disease models." Autophagy 13, no. 12 (December 2, 2017): 2028–40. http://dx.doi.org/10.1080/15548627.2017.1379633.

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10

Matsushima, Takahide, Tadashi Nakaya та Toshiharu Suzuki. "P1-155: Exclusion of phosporylated APP CTFs from membrane region rich in active γ-secretase". Alzheimer's & Dementia 5, № 4S_Part_7 (липень 2009): P223. http://dx.doi.org/10.1016/j.jalz.2009.04.161.

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Дисертації з теми "APP-CTFs":

1

Mary, Arnaud. "Implications de la signalisation de la protéine kinase activée par l’AMP (AMPK) dans les dysfonctions mitochondriales, la pathologie amyloïde et Tau, et la neuroinflammation dans la maladie d’Alzheimer." Thesis, Université Côte d'Azur, 2022. http://theses.univ-cotedazur.fr/2022COAZ6001.

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La maladie d’Alzheimer (MA) est la pathologie neurodégénérative la plus répandue dans le monde. L’échec des traitements ciblant l’amyloïde beta (Aβ), un catabolite de la protéine précurseur de l’amyloïde (APP), souligne le caractère multifactoriel de cette pathologie. Ainsi, les défauts précoces de la structure et de la fonction des mitochondries et la neuroinflammation sont impliqués dans le développement de la MA. Différentes études décrivent l’AMPK (AMP-activated protein kinase) comme étant un acteur majeur de l'homéostasie mitochondriale notamment via l’élimination des mitochondries altérées par mitophagie et dans la régulation de la neuroinflammation.L'hypothèse centrale de mon projet postule qu'outre le peptide Aβ, d'autres catabolites de l'APP, les fragments C-terminaux (APP-CTFs) peuvent contribuer aux dysfonctions mitochondriales et aux défauts de la mitophagie, et que la modulation de l’AMPK pourrait avoir un impact bénéfique dans le contexte de la MA.Ma thèse est structurée en deux objectifs spécifiques :Axe 1. Étude de la contribution des APP-CTFs dans les défauts de la structure et de la fonction des mitochondries et de la mitophagie dans la MA. Nous avons observé une accumulation des APP-CTFs dans la mitochondrie des cellules de neuroblastomes humains exprimant de façon stable l’APP portant la double mutation suédoise (SH-SY5Y-APPswe), ou le fragment APP-CTFβ : C99 (SH-SY5Y-C99) entraînant une altération de la morphologie des mitochondries, une augmentation de la production d’espèces réactives de l’oxygène (ROSmit) et un blocage de la mitophagie. Ces effets toxiques ont été confirmés chez les souris présymptomatiques 3xTgAD (APPswe, TauP301L, PS1 (M146V)) et des souris exprimant le fragment C99 par une approche virale, et sont exacerbés (in vitro et in vivo) suite à l’inhibition de la γ-sécrétase, bloquant la production du peptide Aβ et accumulant les APP-CTFs. Enfin, l’analyse des nécropsies de cerveaux de patients humains diagnostiqués avec une forme sporadique de la MA, a montré une accumulation des APP-CTFs dans les mitochondries, corrélant avec un défaut du processus mitophagique. Ainsi, cibler l’accumulation précoce de ces APP-CTFs et la dysfonction mitochondriale pourraient représenter de nouvelles cibles thérapeutiques dans le contexte de la MA.Axe 2. Étude de l'impact de la modulation de la cascade de signalisation de l'AMPK dans le contexte de la MA. Nous avons observé une répression de la cascade AMPK-ULK1 dans les nécropsies de lobes temporaux de patients Alzheimer sporadiques, dans les modèles d’étude de la MA in vitro (SH-SY5Y-APPswe et SH-SY5Y-C99), et chez les souris symptomatiques 3xTgAD. Nous avons démontré que l’inhibition pharmacologique de l’AMPK augmente l’accumulation des APP-CTFs, exacerbe les défauts de la structure des mitochondries, provoque une hyperpolarisation de la membrane mitochondriale et une augmentation de la production de ROSmit, et inhibe la mitophagie dans les modèles in vitro. L’inhibition pharmacologique de l’AMPK affecte également la maturation des épines dendritiques ex vivo (coupes organotypiques d’hippocampes exprimant l’APPswe par une approche virale). A l’inverse, l’activation pharmacologique de l’AMPK permet de réduire le dysfonctionnement mitochondrial (in vitro), de favoriser la maturation des épines dendritiques (ex vivo). Nous avons confirmé ces observations par une approche génétique en exprimant des constructions AMPK mutées (formes constitutive active et dominante-négative). De façon importante, l’activation pharmacologique de l’AMPK in vivo a permis de réduire la pathologie Aβ et Tau, ainsi que la neuroinflammation et les défauts d’apprentissage chez les souris 3xTgAD symptomatiques. Ainsi, la stimulation de l’AMPK pourrait représenter une nouvelle piste thérapeutique réduisant plusieurs paradigmes associés à la MA
Alzheimer’s disease (AD) is the most common neurodegenerative disease in the world. Failures of candidate treatments targeting the beta amyloid (Aβ), a catabolite originating from the amyloid precursor protein (APP), highlight the multifactorial nature of this pathology. Hence, the early defects of mitochondrial structure and functions, and the neuroinflammation are implicated in AD development. Several studies describe the AMPK (AMP-activated protein kinase) as a master regulator of mitochondrial homeostasis, notably via the elimination of damaged mitochondria by mitophagy, and also of neuroinflammation. The central hypothesis of my thesis postulates that, besides the Aβ peptide, other APP catabolites, the C-terminals fragments (APP-CTFs) can contribute to mitochondrial dysfunctions and that the modulation of the AMPK could hold beneficial effects in AD.My thesis is structured into two specific objectives:Axe 1. Study of the APP-CTFs contribution to the alterations of mitochondria structure, functions, and mitophagy in AD. We have observed an accumulation of APP-CTFs in mitochondria of human neuroblastoma cells stably expressing APP with the double Swedish mutation (SH-SY5Y-APPswe), or the APP-βCTF: C99 (SH-SY5Y-C99), causing an alteration of mitochondria morphology, an increase reactive oxygen species (ROSmit) production, and a blockade of mitophagy. These toxic effects were confirmed in presymptomatic 3xTgAD mice (APPswe, TauP301L, PS1 (M146V)) and in mice expressing the C99 fragment via a lentiviral approach and were exacerbated (in vitro and in vivo) following the inhibition of the γ-secretase, blocking the Aβ production and accumulating APP-CTFs. Finally, we have reported a mitochondrial accumulation of APP-CTFs in the temporal lobes necropsies of sporadic AD patients correlating with a defective mitophagic phenotype. Hence, targeting the early APP-CTFs accumulation and mitochondrial dysfunctions could constitute promising novel therapeutic targets in the AD context.Axe 2. Study of the impact of AMPK signaling cascade modulation in AD. We have observed a defective AMPK-ULK1 cascade in the temporal lobes necropsies of sporadic AD patients, in in vitro AD study models (SH-SY5Y-APPswe and -C99) and in symptomatic 3xTgAD mice. Afterward, we have demonstrated that the pharmacological inhibition of AMPK enhances APP-CTFs accumulation, worsen mitochondria structure alterations, triggers mitochondria membrane hyperpolarization, increases ROSmit production, and inhibits mitophagy in vitro. Pharmacological AMPK blockade also alters the dendritic spine maturation ex vivo (organotypic hippocampal slices lentivirally expressing APPswe). Oppositely, the pharmacological activation of AMPK alleviates mitochondria dysfunctions in vitro and favors the dendritic spine maturation ex vivo. We confirmed these observations using a genetic approach by expressing mutated AMPK constructs (constitutive active and dominant negative forms). Importantly, pharmacological activation of AMPK reduces Aβ and Tau pathologies, as well as neuroinflammation and learning impairments in symptomatic 3xTgAD mice. Overall, the stimulation of AMPK could stand as a new therapeutic avenue to alleviate AD pathogenesis
2

Bécot, Anaïs. "Les APP-CTFs au cœur du processus pathologique de la maladie d’Alzheimer : contribution du système lysosomal-autophagique et de la sécrétion exosomale." Thesis, Université Côte d'Azur (ComUE), 2019. http://theses.univ-cotedazur.fr/2019AZUR6039.

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La maladie d’Alzheimer (MA) se caractérise par l’accumulation dans le cerveau d’agrégats extracellulaires et intraneuronaux (Aβ et Tau). Dans la cellule, la principale voie de dégradation des protéines agrégées est la voie lysosomale-autophagique, qui est altérée de façon précoce chez les patients Alzheimer. Des études récentes de mon laboratoire ont montré que ce dysfonctionnement serait à la fois la cause et la conséquence de l’accumulation du précurseur direct de l’Aβ, appelé C99 ou APP-CTFβ. De par sa toxicité, le C99 semble donc jouer un rôle crucial dans l’étiologie de la maladie. Son accumulation se produit majoritairement dans les compartiments endolysosomaux mais de façon intéressante, un marquage extracellulaire associé au C99 a également été observé à des stades plus avancés de la maladie ou en présence d’un inhibiteur de la γ-sécrétase (enzyme clivant le C99 en Aβ). Le premier axe de mon travail de thèse a donc consisté à étudier l’efficacité d’une restauration du système lysosomal-autophagique sur l’accumulation du C99. Dans ce but, nous avons utilisé une stratégie virale visant à exprimer le facteur de transcription EB (TFEB) dans un modèle murin de la MA (3xTg-AD). Ce facteur est le principal régulateur de la biogenèse lysosomale et de l’autophagie. Deux approches ont été testées cherchant à exprimer le TFEB avant ou après le début de l’accumulation du C99, grâce à une injection de virus exprimant le TFEB, soit en intracérébroventriculaire dès la naissance, soit par stéréotaxie à l’âge de 4 mois. Ces études ont montré une réduction importante de l’accumulation intraneuronale du C99 chez les souris 3xTg-AD, que ce soit via l’approche "préventive" ou "curative". Le deuxième axe de mon travail de thèse a cherché à comprendre l’origine du marquage extracellulaire observé dans le cerveau et associé au C99. Nous avons émis l’hypothèse que ce marquage correspondrait à des exosomes enrichis en C99. Les exosomes sont des vésicules extracellulaires, d’origine endosomale et sécrétées par les cellules, ayant déjà été décrites comme transportant des protéines neurotoxiques. Grâce à des approches pharmacologiques, immunocytochimiques et génétiques, nous avons confirmé cette hypothèse et mis en évidence la présence de C99 et de son dérivé le C83 (APP-CTFα) dans les exosomes purifiés à partir de modèles cellulaires ou murins de la MA, sous forme monomérique et oligomérique. Nos travaux montrent également que la charge des exosomes en oligomères est fortement amplifiée en présence d’une inhibition de la γ-sécrétase, expliquant ainsi le marquage extracellulaire. En conclusion, mes travaux de thèse (1) proposent une potentielle stratégie thérapeutique, basée sur l’activation du TFEB et visant à empêcher l’accumulation du C99, (2) montrent la présence de monomères et d’oligomères de C99 dans les exosomes ainsi qu’un lien entre la γ-sécrétase et l’oligomérisation. Les futures études devront déterminer le rôle exact de ces exosomes enrichis en C99
Alzheimer’s disease (AD) is characterized by the pathological accumulation of extracellular and intracellular aggregates (Aβ and Tau) in the brain. AD is also associated with an early alteration of the major degradation pathway of aggregated proteins, the autophagic-lysosomal pathway. Recent works have suggested that this defectcouldbothbeacauseandaconsequenceofearlyintraneuronalaccumulation of C99 (also named as APP-CTFβ), the direct precursor of Aβ. Due to its toxicity, C99 could be a possible key player of AD etiology. The accumulation of this product occurs mainly within organelles of the endolysosomal network, but our recent observations also indicate an extracellular accumulation of C99 in later stages of the disease, or in conditions where the Aβ-generating enzyme, γ-secretase, is blocked. The first aim of my PhD project was to investigate the possible beneficial effect of restoringlysosomal-autophagicfunctiononC99accumulation. Tothisend, weused a viral strategy to overexpress TFEB, a master regulator of both lysosome biogenesis and autophagy, in a mouse model of AD (3xTg-AD mouse). Two approaches were tested aiming to express TFEB either before or after the beginning of C99 accumulation, by injecting AAV-TFEBs into the ventricles of newborn mice or by stereotaxic injection into 3 month-old mice, respectively. These studies have shown a strong TFEB-mediated reduction of C99 accumulation when using both the preventive and curative approach. The aim of the second part of my PhD work was to understand the reasons of the extracellular accumulation of C99. We postulated that this C99-associated immunostaining could correspond to exosomal-associated C99. Exosomes are nanosizedvesiclesofendocyticoriginthatarereleasedfromcellsandknowntotransport neurotoxic proteins. In our study based on pharmacological, immunocytochemical and genetic approaches, we have confirmed this hypothesis and have shown the presence of C99, and of its direct derived-fragment C83 (APP-CTFα), existing as both monomers and oligomers, in exosomes purified from AD cell and mouse models. Moreover, our data have shown that the levels of these APP-CTFs are strongly increased by γ-secretase inhibition, thus explaining the higher levels of extracellular staining in γ-secretase treated animals. In conclusion, my PhD work shows 1) a new potential therapeutic strategy based on TFEB activation aiming to reduce early C99 accumulation and 2) the presence of monomeric and oligomeric C99 in exosomes in AD models and a link between γ-secretase inhibition and oligomerisation. Future studies are needed to elucidate the exact role of these C99-enriched exosomes in AD
3

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

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