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Maladie d'Alzheimer : Impact extracellulaire et intracellulaire du peptide ß-amyloïde sur la transmission synaptique glutamatergique

Abstract : Alzheimer’s disease (AD) is the most common form of dementia associated with memory loss and characterized by an accumulation of extracellular plaques composed of amyloid-beta peptides (Aβ). Studies have revealed a greater loss of synapses than the neuronal death can explain, suggesting that a synaptic deficit would be present from the early stages of the disease. Although the Aβ peptide has been identified as a component of the extracellular amyloid plaques in the 1980s, recent studies have highlighted the intracellular presence of this peptide. The intracellular accumulation of Aβ precedes the appearance of amyloid plaques in the pathogenesis of AD and seems to be correlated with the memory and learning troubles, characteristic of this disease. Moreover, some data highlight the responsibility of the soluble oligomeric Aβ form (Aβo) in the early events of AD. This project aims to better understand and characterize the extracellular and intracellular impact of Aβo peptides and the functional link of their effects on the molecular mechanisms involved in memory processes affected in AD. In this context, it was essential to study the extracellular and intracellular impact of Aβ oligomers on synaptic transmission. This work was carried out on cultures of primary cortical neurons and mouse cortex slices using electrophysiological methods via the patch-clamp technique.We have recorded the spontaneous excitatory postsynaptic currents (sEPSC) frequency and amplitude from the main receptors implicated in the glutamatergic transmission and in the molecular mechanisms underlying memory and learning processes: AMPA and NMDA receptors. Our data show that external or internal application of Aβo peptides affect specifically the currents associated with NMDA receptors at a postsynaptic level without altering the AMPA currents. The external application of Aβo reduces the NMDA current amplitude. This phenomenon is not due to the penetration of the Aβo peptide into the neurons but rather to the activation of the amyloïdogenic pathway by Aβo inducing an intracellular accumulation of Aβo responsible of the NMDA current reduction.All these data suggest that Aβo perturb the processing of APP leading to an intracellular Aβo production responsible of the glutamatergic NMDA-dependent transmission reduction. An essential step in order to improve our understanding of the molecular mechanisms underlying the altered glutamatergic synaptic alterations found in AD is to deepen the functional link between the extracellular and intracellular effects of the Aβo peptides.
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Submitted on : Tuesday, January 16, 2018 - 11:46:06 AM
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  • HAL Id : tel-01685279, version 1




Marta Rolland. Maladie d'Alzheimer : Impact extracellulaire et intracellulaire du peptide ß-amyloïde sur la transmission synaptique glutamatergique. Médecine humaine et pathologie. Université Grenoble Alpes, 2016. Français. ⟨NNT : 2016GREAV034⟩. ⟨tel-01685279⟩



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