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Altérations des synapses et des corps cellulaires neuronaux chez les souris APPxPS1-KI et dans la Maladie d'Alzheimer

Abstract : Alzheimer’s Disease (AD) is characterized by a progressive loss of synapses and neurons. The loss of synapses is an early marker significantly correlating with cognitive decline in patients. How the Amyloid Precursor Protein (APP) cleavage product Amyloid Beta (Abeta) can trigger synapse and neuron loss remains debated. We investigated this mechanism in APPxPresenilin1 knock-in (APPxPS1-KI) mice that were previously shown to present with a loss of pyramidal neurons in the CA1 hippocampus. We observed that this loss of neurons was preceded by a loss of synapses in the stratum radiatum of CA1. We showed that these losses were not induced by an endoplasmic reticulum stress and we did not observe depression of synaptic activity or increase of long-term depression. Alterations of dendritic spine morphology were observed before the loss of synapses and neurons along with a deficit of long-term potentiation and spatial memory troubles. Similar dendritic spines morphological alterations were observed in cortical biopsies from AD patients. In mice, these alterations changed electrical and biochemical compartmentalization of the spines, potentially implicated in long-term potentiation. In APPxPS1-KI neuronal cell bodies, an accumulation of Abeta was observed in the lysosomes. A modification of the lysosomal system was also observed in biopsies from patients. The alterations of the lysosomal system were specifically observed in APPxPS1-KI mice and could be implicated in the loss of synapses and neurons.
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Alexandre Androuin. Altérations des synapses et des corps cellulaires neuronaux chez les souris APPxPS1-KI et dans la Maladie d'Alzheimer. Neurosciences [q-bio.NC]. Sorbonne Université, 2018. Français. ⟨NNT : 2018SORUS547⟩. ⟨tel-02924681⟩

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