Overexpression of APP soluble forms : physiological roles and application to Alzheimer’s disease ; Conséquences de la surexpression des formes solubles de l’APP dans les mécanismes de mémoire : application à la maladie d'Alzheimer
In: https://theses.hal.science/tel-01731051 ; Neurosciences. Université Sorbonne Paris Cité, 2016. Français. ⟨NNT : 2016USPCB047⟩, 2016
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Zugriff:
One of the main characteristic of Alzheimer’s Disease (AD) is the intracerebral accumulation of the neurotoxic Amyloid β peptide (Aβ) either as oligomeric or aggregated forms known as the amyloid plaques. This peptide is produced via the Amyloid Precursor Protein (APP) processing following the amyloidogenic pathway, pathological pathway overactivated in AD. Most of the research performed during the last 25 years focused on pathogenic consequences of this dysregulation, deprioritizing the understanding of the APP physiological functions. Nonetheless, numerous studies show that these physiological functions might be mediated via APP soluble forms (APPs). In the physiological APP processing pathway, the non-amyloidogenic pathway, APP is cleaved by the α secretase, releasing the APPsα which display neuroprotective and synaptotrophic properties, essential for brain normal functions. In the context of AD, the amyloidogenic pathway overactivation leads to APPsβ overproduction at the expense of APPsα. Therefore, AD harmful consequences could be due to the decrease of APPsα concentration associated with an increase of APPsβ. My thesis project aimed to characterize mnemonic and functional properties following the overexpression of these two soluble forms of APP and their therapeutic potential in AD. We firstly overexpressed APPsα in hippocampal neurons of APP/PS1ΔE9 mice, animal model of AD, which display cognitive and synaptic deficits. The continual expression of APPsα, mediated via AAV viruses, enabled restoration of spatial memory, long-term potentiation and dendritic spines density in the hippocampus. This phenotypic rescue was accompanied with the decrease of both Aβ levels and amyloid plaques. This might be due to the activation of microglia, cell type able to internalize and degrade Aβ. In a second hand, I studied the involvement of APPsβ in AD, which remains poorly known. Its overexpression in APP/PS1ΔE9 did not induce neither LTP nor spatial memory restoration. However, APPsβ injection lead to the decrease of Aβ ...
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Overexpression of APP soluble forms : physiological roles and application to Alzheimer’s disease ; Conséquences de la surexpression des formes solubles de l’APP dans les mécanismes de mémoire : application à la maladie d'Alzheimer
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Autor/in / Beteiligte Person: | Fol, Romain ; Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN) ; Service MIRCEN (MIRCEN) ; Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB) ; Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS) ; Université Sorbonne Paris Cité ; Cartier, Nathalie |
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Zeitschrift: | https://theses.hal.science/tel-01731051 ; Neurosciences. Université Sorbonne Paris Cité, 2016. Français. ⟨NNT : 2016USPCB047⟩, 2016 |
Veröffentlichung: | HAL CCSD, 2016 |
Medientyp: | Hochschulschrift |
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