Job: PhD – Study in rodents of a new synaptic signaling mechanism involving APP and H₂O₂ (M/F)

About

Description of the thesis topic

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory impairment. AD is linked to the accumulation of amyloid-beta (Ab) peptides, derived from the transmembrane protein Amyloid-beta Precursor Protein (APP). The origin of AD remains enigmatic, and, in particular, the mechanisms by which Ab affects synaptic plasticity are still the subject of intense debate.
We recently unveiled a neuronal plasticity mechanism essential for the formation of long-term memory 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, Ab inhibits ANHOS by interacting with the acetylcholine receptor α7 (AChRa7), expressed in astrocytes.
Our discovery opens up the intriguing possibility that, in humans, Alzheimer's disease (AD) may initially be linked to a deficiency in beneficial reactive oxygen species (ROS), with the oxidative stress observed in AD being a secondary effect. The objectives of this thesis project will be to define the role played by this new mechanism in the mammalian brain (the mouse). It will be divided into three main areas:
1) Evaluate 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.
2) Test the relationship between acetylcholine and ROS in hippocampal neurons, by chemogenetically activating cholinergic afferents and performing in vivo imaging of ROS levels.
3) 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 the APP protein in neuron-glia interactions and on Aβ-induced synaptic defects in Alzheimer's disease.

Apply directly on the CNRS job portal

https://emploi.cnrs.fr/Offres/Doctorant/UMR7275-HELMAR-005/Default.aspx