Description du sujet de thèse

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory deficits. AD is linked to the accumulation of amyloid-β (Aβ) peptides, derived from the transmembrane Amyloid-beta Precursor Protein (APP). The origin of AD remains elusive and, more specifically, the mechanisms by which Aβ affects synaptic plasticity are still the subject of intense debate.

We recently uncovered a neuronal plasticity mechanism essential for long-term memory formation in Drosophila. This mechanism, which forms the basis of our project, involves the local synthesis of beneficial reactive oxygen species (ROS) through astrocyte–neuron interactions. We showed that APP plays a central role in this astrocyte-to-neuron H₂O₂ signaling cascade (ANHOS) via its extracellular copper-binding E2 domain. Conversely, Aβ inhibits ANHOS by interacting with the α7 nicotinic acetylcholine receptor (AChRα7), expressed in astrocytes.

Our discovery raises the intriguing possibility that, in humans, AD may initially be linked to a deficit in beneficial ROS, with the oxidative stress observed in AD being a secondary effect. The objectives of the PhD project will be to define the role played by this novel mechanism in the mammalian brain (mouse). It will be divided into three main aims:

Assess the role of local ROS synthesis in synaptic plasticity and memory by selectively removing proteins involved in this synthesis and combining electrophysiological and behavioral analyses.

Test the relationship between acetylcholine and ROS in hippocampal neurons by chemogenetically activating cholinergic afferents and performing in vivo imaging of ROS levels.

Examine how Aβ disrupts the ANHOS mechanism, focusing on its interaction with nAChRα7 receptors and its impact on synaptic function in sensitized mouse models.

This project will shed entirely new light on the physiological function of APP in neuron–glia interactions and on the synaptic defects induced by Aβ in Alzheimer's disease

Contexte de travail

Work in biology laboratory - 100% on site.

Le poste se situe dans un secteur relevant de la protection du potentiel scientifique et technique (PPST), et nécessite donc, conformément à la réglementation, que votre arrivée soit autorisée par l'autorité compétente du MESR.

Contraintes et risques

Biological and chemical risks