Projektbeschreibung
Ist Kupfer ein mögliches therapeutisches Ziel für Alzheimer?
Bei der Alzheimer-Krankheit handelt es sich um eine neurodegenerative Störung, die mit einer abnormen Anhäufung des Amyloid-Beta-Peptids einhergeht. Neue Erkenntnisse deuten darauf hin, dass Metallionen, vor allem Kupfer und Zink, an das Amyloid-Beta-Peptid binden. Im Rahmen des vom Europäischen Forschungsrat finanzierten Projekts aLzINK wird von der Hypothese ausgegangen, dass diese Metallionen die Pathophysiologie von Alzheimer beeinflussen. Hauptziel ist die Untersuchung der zugrunde liegenden Mechanismen, der Art der Bindungen und der möglichen toxischen Auswirkungen dieser Metallionen. Darüber hinaus werden die Forschenden neue Wirkstoffkandidaten entwickeln, die selektiv auf das an Amyloid beta gebundene Kupfer (im Gegensatz zu Zink) abzielen, um dessen schädliche Wirkung zu beeinträchtigen.
Ziel
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...
Wissenschaftliches Gebiet
- 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
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-STG - Starting GrantGastgebende Einrichtung
75794 Paris
Frankreich