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Christelle HUREAU

Team leader

Coordination Chemistry Lab - UPR 8241
205 Route de Narbonne
31077 Toulouse - Cedex 04 - France
(+33) 5 61 33 31 62
[christelle.hureau@lcc-toulouse.fr]

Research

My main research interest concerns the role of metal ions, mainly Cu and Zn in the amyloid cascade process linked to the etiology of Alzheimer's disease (AD). According to the amyloid cascade (Figure 1), metal ions which are exchanged within the synaptic cleft where the amyloid-β peptides (Aβ) is present are involved in two deleterious events encountered in AD: the self-assembly of Aβ and the production of Reactive Oxygen Species by Cu-bound Aβ.

1-Metal ions binding to the amyloid-b peptides. Seminal results were the determination by EPR, NMR and XAS of the Cu(II), Cu(I) and Zn(II) coordination spheres and affinity values when bound to the human Aβ peptide and other biologically relevant Aβ peptides (truncated forms, murine variants, etc.). For recent reviews, see: Coord. Chem. Rev. 2018, eicb 2018.  More recently, I have been interested in the description of kinetics of metal exchange between Aβ and other biomolecules (Inorg Chem 2021).

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Figure 1. The amyloid cascade process.

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Figure 2. Scheme of the in-between state (IBS) responsible for ROS production and of its equilibria with the resting (RS) in Cu(II) and Cu(I) redox state.

2-ROS production. The nature of the coordination sites of the Cu(I) and Cu(II) ions to the Aβ affect the production of Reactive Oxygen Species (ROS). We have proposed that a peculiar mechanism where the metal site goes through an intermediate geometry in which it becomes catalytic (named “in-between state”) and we have recently deduced the environment of the copper center in the in-between state from complementary analytical methods (Reviewed in Chem. Soc. Rev. 2023, and see Anal. Chem. 2018, Chem. Sci. 2017 and PNAS 2010).

3-Self-assembly of amyloid-forming peptides. This process is at the core of several, so-called, amyloid diseases. The diseases are peptide-dependent and the deposits of b-sheet-rich fibrils are localized at different places, e.g. in the pancreas in case of type 2 diabetes and in the brain in case of AD. Metal ions do modify the self-assembly process as do other synthetic modulators and biological chaperones. Metal ions favor intermediates (oligomeric Aβ) regarded as the most toxic species. Being able to reproduce the self-assembly process in vitro is highly challenging (FrontiersChem 2021). This is due the self-catalytic nature of the process in linked with secondary nucleation paths (Fig. 3). We have shown that metal ions modulate the self-assembly paths (CEJ 2021) and we are currently investigating cross-talk between two amyloid-forming peptides in co-assembly process (Projet Amyl-in-AD, MITI CNRS).

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Figure 3. Self-assembly of amyloid-forming peptides showing the nucleation-elongation mechanism and the secondary nucleation processes. Species present during the various assembly steps are shown in the three boxes, while the intermediates are regarded as the most neurotoxic species.

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Figure 4. Scheme recapitulating some of the requirements of Cu-targeting molecules in the context of AD (From Inorg.Chem. 2019).

4-Therapeutic approaches. Because the interaction of Cu with the Aβ peptide is regarded as toxic, we have studied several proofs of concept regarding chelation and its extraction out of Aβ. The most important one is the interference of Zn(II) in Cu chelation (DaltonTrans 2016, DaltonTrans 2017, CEJ 2018, InorgChem 2021) and removal from the Aβ peptide, Cu being considered as the target of choice due to its ability in ROS formation. We have also shown that Cu(I) (in addition to Cu(II)) should be considered in chelation therapy (Metallomics 2016, Metallomics 2019, CEJ 2017, CEJ 2020), that kinetic aspects are also be important (CEJ 2017) and that inorganic prodrugs able to mask the toxicity of the ligand is an interesting strategy (CEJ 2018). Other strategies are currently under investigation.

5-Detection approaches. The early detection is a key point for setting up therapeutic lines in due time. We have a recently illustrate that point in case of Gd(III) complexes for further MRI studies (CEJ 2021).  We are currently investigating compounds able to probe selectivity different kinds of amyloids.

Summary of the ERC-funded aLzINK project :

CV

Publications

>130 international peer-reviewed publications: 1 Acc. Chem. Res. ; 4 Anal. Chem.; 6 Angew. Chem. Int. Ed.; 5 Chem. Commun.; 3 Chem. Soc. Rev.; 2 Chem. Sci. ; 17 Chem. Eur. J.; 24 Inorg.Chem.; 1 Redox Biology; including 10 publications highlighted in covers

+ 6 book chapters & 18 international conference proceedings referenced in the WoS database.

64 publications as corresponding authors; 18 as first author & 51 at last author.

H-index: 43, and average citations: 43; citations: > 6500 (without self-citations: > 5500)

10 main publications as corresponding author:

   Falcone, E.; Hureau, C.* “Redox processes in Cu-binding proteins: the “in-between”states in intrinsically disordered peptides” Chem. Soc. Rev. (viewpoint), in press, 10.1039/D3CS00443K

  Malikidogo, K. P.; Drommi, M.; Atrián-Blasco, E.; Hormann, J.; Kulak, N.; Esmieu, C.*; Hureau, C.* “Ability of Azathiacyclen Ligands To Stop Cu(Aβ)-Induced Production of Reactive Oxygen Species: [3N1S] Is the Right Donor Set” Chem. Eur. J. 2023, 29, e202203667 (cover picture), 10.1002/chem.202203667

   Cheignon, C., Collin, F.; Sabater, L.; Hureau, C.* “ Oxidative Damages on the Alzheimer’s Related-Aβ Peptide Alters Its Ability to Assemble” Antioxydants 2023, 12, 472, 10.3390/antiox12020472

   Atrián-Blasco, E.; de Cremoux, L.; Lin, X.; Mitchell-Heggs, R.; Sabater, L.; Blanchard, S.*; Hureau, C.* “Keggin-type polyoxometalates as Cu(II) chelators in the context of Alzheimer's disease” Chem. Commun. 2022, 58, 2367-70, 10.1039/D1CC05792H

   Behar, A. E.; Sabater, L.; Baskin, M.; Hureau, C.*; Maayan, G.* “A Water-Soluble Peptoid Chelator that Can Remove Cu(II) from Amyloid-β Peptides and Stop the Formation of Reactive Oxygen Species Associated with Alzheimer's Disease” Angew. Chem. Int. Ed, 2021, 60, 24588-97, 10.1002/anie.202109758

6    Stefaniak, E.; Atrian-Blasco, E.; Goch, W.; Sabater, L.; Hureau, C.*; Bal, W.* “The Aggregation Pattern of Aβ1‑40 is Altered by the Presence of N-Truncated Aβ4-40 and/or Cu(II) in a Similar Way through Ionic Interactions” Chem. Eur. J. 2021, 27, 2798-09, 10.1002/chem.202004484

7    Cheignon, C.; Jones, M.; Atrian-Blasco, E.; Kieffer, I.; Faller, P.; Collin, F.; Hureau, C.* "Identification of key structural features of the elusive Cu-Aβ complex that generates ROS in Alzheimer's disease" Chem. Sci. 2017, 8, 5107-18, 10.1039/c7sc00809k

   Alies, B.; Sasaki, I.; Proux, O.; Sayen, S.; Guillon, E.; Faller, P.; Hureau, C.* "Zn impacts Cu coordination to amyloid-beta, the Alzheimer's peptide, but not the ROS production and the associated cell toxicity" Chem. Commun. 2013, 49, 1214-6, 10.1039/c2cc38236a

9    Eury, H.; Bijani, C.; Faller, P.; Hureau, C.* "Copper(II) coordination to amyloid beta: murine versus human peptide" Angew. Chem. Int. Ed. 2011, 50, 901-5, 10.1002/anie.201005838

10  Hureau, C.*; Coppel, Y.; Dorlet, P.; Solari, P.-L.; Sayen, S.; Guillon, E.; Sabater, L.; Faller, P.* "Deprotonation of the Asp1-Ala2 peptide bond induces modification of the dynamic copper(II) environment in the Aβ peptide near physiological pH" Angew. Chem. Int. Ed. 2009, 48, 9522-5, 10.1002/anie.200904512

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