0561333162Présentation
HUREAU-SABATER Christelle (40 years old)
Team leader of the “Alzheimer and amyloids”
Coordination Chemistry Lab - UPR 8241
205 Route de Narbonne
31077 Toulouse - Cedex 04 - France
(+33) 5 61 33 31 62
[christelle.hureau chez lcc-toulouse.fr]
Main research thematic.
My main research interest concerns the impact of metallic ions, mainly Cu, Zn and Fe on the amyloid cascade process linked to the etiology of Alzheimer’s disease (AD). According to the amyloid cascade (Figure 1), metallic ions are involved in two deleterious events encountered in AD : the aggregation of the amyloid-β peptide (Aβ) and the production of Reactive Oxygen Species by metallated Aβ species.
Fig. 1. The amyloid cascade process.
Fundamental studies.
* In this thematic, the main recent results are the determination by EPR, NMR and XAS of the Cu(II), Cu(I) and Zn(II) coordination spheres when bound to the human Aβ peptide and other biologically relevant Aβ peptides (truncated forms, murine…). These results are reviewed in Coord. Chem. Rev. 2012, 256, p 2164, 2175.
* Impact of coordination of the Cu(I) and Cu(II) ions on the production of Reactive Oxygen Species has been studied. A peculiar mechanism where the metal site goes through an intermediate geometry in which it becomes catalytic is proposed (Figure 2). See Angew. Chem. Int. Ed., 2013, 52, p 11110.
Fig. 2. ROS production mechanism.
* Impact of Zn and Cu binding to the aggregation of Aβ peptides are studied by ThT fluorescence and TEM and AFM microscopies. pH, global net charge and metallic ion coordination sphere have been identified as important parameters. See Inorg. Chem., 2012, p 701-708 ; 7897-7902.
* Studies implying both metal ions (Cu AND Zn) are underway.
Toward therapeutic approaches.
* We study several proof of concepts regarding chelation. The most important one is the interference of Zn(II) in Cu chelation and removal from the Aβ peptide, Cu being considered as the target of choice due to its redox ability (Figure 3). See Dalton Trans. 2016, 45, p 15671.
Fig. 3. Illustration of the possible interference of Zn(II) in copper detoxification (when the ligand is not selective enough for Cu(II)).
* Systems able to transport Cu from the outside to the inside of the neurons are also of interest since an intra-neuronal deficit in Cu(I) ion has been reported in the AD context. Peptidic scaffolds are well suited to do so (Figure 4, studies in collaboration with Pr. P. Faller, Strasbourg).
Fig. 4. Illustration of the metallophore strategy.
We also consider the development of bifunctional Cu chelators aiming to retrieve specifically ions bound to the aggregated states of Aβ.
Finally, we develop artificial chaperones of the Aβ peptides aggregation that inhibit the auto-assembly process. Studies with Pt, Ru, Ln-based and POM species are considered.
Toward diagnostic approaches.
* Ln-based MRI agents are currently being developed to image another kind of amyloids deposits made of the amyloidogenic peptide IAPP (amylin) encountered in Type II-diabetes.
Fig. 5. Model mouse of T2-diabete and scheme of Ln-based probe incorporating an amylin targeting moiety.
* The development of new aggregation markers is also undertaken based on a 2-aryl-benzothiazole moiety linked to various kind of probes (EPR, photo-affinity, redox) (Figure 6) in order to find alternative ways to monitor the aggregation process and new ones to detect the oligomeric species.
Fig. 6. 2-aryl-benzothiazole moiety linked to various kind of probes.
Side-project.
As a side project, Mn and Fe based catalase mimics (Figure 7) are characterized by several complementary techniques while the complexes are designed and synthesized in Argentina where their catalase activity is also tested (Collaboration Pr. S. Signorella). See Coord. Chem. Rev., 2012, pp1229-1245. Mn-based water oxidizing mimic complexes are studied as well.
Fig. 7. X-ray structure of a water-soluble catalase mimics.
