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The role of Abeta peptide of Alzheimer disease on the cellular basis of learning and memory in an Amyloid Precursor Protein (APP) Knock-out mouse

Objectifs

Evaluate the impact of A? peptide on dendritic spine morphology and synaptic plasticity in neuronal cultures and brain slices from APP Knock-out mice.

Résumé

Amyloid-? (A?) drives the synaptic impairment and dendritic spine loss characteristic of Alzheimer’s disease (AD). We showed recently that application of A? oligomers on both neuronal cultures and brain slices reduces glutamatergic transmission. This effect does not require the uploading of A? oligomers into the neurons but rather the activation of the APP processing towards the amyloïdogenic pathway. Interestingly, these defaults of synaptic transmission are associated with an alteration of dendritic spine morphology observed in neuronal culture. Together, these data reveal that extracellular A? oligomers trigger a vicious circle that disrupt synaptic glutamatergic neurotransmission contributing to the spreading of the disease. To confirm that these alterations are related to the processing of APP, we will test the impact of A? peptide on synaptic plasticity and dendritic spine morphology in neuronal cultures and brain slices from APP Knock-out mice. By targeting this mechanism, we may stop the propagation of the excitatory neurotransmission deficit that characterizes the early stages of Alzheimer disease.

Méthodes

We will use different electrophysiological techniques to measure basal glutamatergic transmission as well as synaptic plasticity potential (Long term potentiation)in physiologic conditions and in the context of Alzheimer’s disease. Subsequently we will study the morphology of dendritic spine by using confocal imaging to determine the relationship between synaptic density and synaptic plasticity potential in wild type, transgenic animals model of AD and APP KO animals.

Références

  • Amar F et al ; The amyloid-? oligomer A?*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. Sci Signal. 2017 May 9;10(478).
  • Lanté F et al ; Subchronic glucocorticoid receptor inhibition rescues early episodic memory and synaptic plasticity deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology. 2015 Jun;40(7):1772-81.
  • Frandemiche ML et al ; Activity-dependent tau protein translocation to excitatory synapse is disrupted by exposure to amyloid-beta oligomers. J Neurosci. 2014 Apr 23;34(17):6084-97.

Contacts

Fabien Lanté, MCF UGA
Email : fabien.lante@univ-grenoble-alpes.fr

Mise à jour le 23 mai 2017

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