Project description
Copper: potential therapeutic target for Alzheimer’s disease?
Alzheimer's disease (AD) is a neurodegenerative disorder associated with the abnormal accumulation of the amyloid beta peptide. Emerging evidence indicates that metal ions, mainly copper and zinc, bind to the amyloid beta peptide. Funded by the European Research Council, the aLzINK project is working under the hypothesis that these metal ions somehow affect AD pathophysiology. The key objective is to study the underlying mechanisms, nature of bindings and possible toxic impact of these metal ions. Moreover, researchers will develop new drug candidates that selectively target copper (versus zinc) bound to amyloid beta, aiming to disrupt its detrimental effects.
Objective
Alzheimer's disease (AD) is one of the most serious diseases mankind is now facing as its social and economical impacts are increasing fastly. AD is very complex and the amyloid-β (Aβ) peptide as well as metallic ions (mainly copper and zinc) have been linked to its aetiology. While the deleterious impact of Cu is widely acknowledged, intervention of Zn is certain but still needs to be figured out.
The main objective of the present proposal, which is strongly anchored in the bio-inorganic chemistry field at interface with spectroscopy and biochemistry, is to design, synthesize and study new drug candidates (ligands L) capable of (i) targeting Cu(II) bound to Aβ within the synaptic cleft, where Zn is co-localized and ultimately to develop Zn-driven Cu(II) removal from Aβ and (ii) disrupting the aberrant Cu(II)-Aβ interactions involved in ROS production and Aβ aggregation, two deleterious events in AD. The drug candidates will thus have high Cu(II) over Zn selectively to preserve the crucial physiological role of Zn in the neurotransmission process. Zn is always underestimated (if not completely neglected) in current therapeutic approaches targeting Cu(II) despite the known interference of Zn with Cu(II) binding.
To reach this objective, it is absolutely necessary to first understand the metal ions trafficking issues in presence of Aβ alone at a molecular level (i.e. without the drug candidates).This includes: (i) determination of Zn binding site to Aβ, impact on Aβ aggregation and cell toxicity, (ii) determination of the mutual influence of Zn and Cu to their coordination to Aβ, impact on Aβ aggregation, ROS production and cell toxicity.
Methods used will span from organic synthesis to studies of neuronal model cells, with a major contribution of a wide panel of spectroscopic techniques including NMR, EPR, mass spectrometry, fluorescence, UV-Vis, circular-dichroism, X-ray absorption spectroscopy...
Fields of science
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- natural scienceschemical sciencesinorganic chemistrybioinorganic chemistry
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesphysical sciencesopticsspectroscopyabsorption spectroscopy
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
Programme(s)
Topic(s)
Funding Scheme
ERC-STG - Starting GrantHost institution
75794 Paris
France