Description du sujet de thèse

The self-assembly of amyloid-β (Aβ) peptide, is dependent on metal ions, mainly copper and zinc, and has long been considered a causal event in Alzheimer's disease (AD). Recent epidemiological data indicate that AD cases are more frequent (approximately +250%) in diabetic patients, suggesting a causal link between the two pathologies, but without a convincing explanation. In type II diabetes, amylin, another peptide with the ability to self-assemble, is overexpressed in response to caloric intake and can cross the blood-brain barrier. Thus, we anticipated that amylin might increase Aβ-related toxicity and participate in the etiology of AD. Our very recent preliminary data show that amylin indeed triggers Aβ self-assembly and is much more toxic than Aβ in cultured hippocampal slices. With the project proposed here, we aim to establish (i) the molecular interactions responsible for the effect of amylin on Aβ assembly, (ii) the mechanisms of toxicity at play on various neuronal model cells and organotypic brain slices, and (iii) the role of metals in (i) and (ii).
The PhD student will work between two teams (INCI Strasbourg and LCC Toulouse) and will study the binding of Cu(II) and Zn(II) to amylin and Aβ peptides and their role in modulating Aβ self-assembly and Aβ/amylin co-assembly in order to determine the interaction between Aβ and amylin, including when mediated by metal ions. Determining the various parameters that govern Aβ and amylin assembly and co-assembly, including in the presence of metal ions, will be an important goal.
Next, the PhD student will evaluate the toxicity of peptides/metal ions on cultured neuronal cells and on hippocampal slices using the previously determined parameters. The state of inflammation will be assessed by measuring the activity of microglial cells. The functional impact on individual neuronal activity and on neural network activity will be measured.

Contexte de travail

The work will be mainly carried out at INCI (Institute of Cellular and Integrative Neurosciences, Strasbourg) and at LCC (Laboratoire de Chimie de Coordination of CNRS (UPR 8241)) in the framework of a collaborative project AMYL-IN-AD funded by the MITI of CNRS. The project will benefit from the infrastructures of the two host teams, the two host laboratories and the platforms available in Strasbourg and Toulouse (Institut de Chimie de Toulouse).

In order to limit the travel of the PhD student between the two sites, the first 16 months will be spent in Toulouse. The remaining 20 months will be spent in Strasbourg. During the three years, regular weekly exchanges between the two co-supervisors and the PhD student are planned using video-conferencing tools. In addition, short stays (about 1 to 2 weeks, once or twice a year) are planned to allow the PhD student to visit the second laboratory.

Contraintes et risques

The work involves exchanges between the two laboratories (Strasbourg and Toulouse) and the manipulation of chemicals/amyloid peptides.

Informations complémentaires

In addition to the procedure through the CNRS portal, the candidate is asked to send a CV and a cover letter including the contact details of one or two referees to vitalen@inci-cnrs.unistra.fr et christelle.hureau@lcc-toulouse.fr.