Project description
Targeting brain metal homeostasis in Alzheimer's disease
Accumulating evidence indicates that loss of neurons in Alzheimer's disease (AD) is a result of oxidative stress driven by active metal ions such as copper on different amyloid beta peptide aggregates. With many trials on AD drugs failing, scientists of the EU-funded TS4NC project are turning to the regulation of metal homeostasis as a treatment option. The new multifunctional S4N agents constitute promising candidates as not only do they chelate copper away from amyloid plaques and provide neuroprotection, but they also redistribute copper ions into the physiological circulation. The TS4NC proposed approach is expected to help restore brain metal homeostasis and open new drug development paths for AD.
Objective
Despite enormous research efforts across academia and pharmaceutical industry, all clinical trials over the last decade have failed in finding a treatment for Alzheimer’s Disease (AD) which remains one of the greatest challenges in drug discovery. Taking consideration all together three prevailing AD hypotheses: Amyloid Cascade, Metal Ions and Oxidative Stress, researchers conclude that loss of neurons is due to a high level of oxidative stress produced by nonregulated redox active metal ions such as copper linked to different forms/aggregates of amyloid-β (Aβ) peptides. Therefore, the regulation of metal homeostasis is a key target for drug development. Herein, we propose a new class of multifunctional agents – S4Ns, which not only sequester Cu ions from their Aβ complexes and arrest their redox cycles, thus reduce oxidative stress in the neuronal cells, inhibit Aβ aggregation, inhibit neuroglia activation and provide anti-inflammatory effects, delivering overall neuroprotection, but also put Cu back into normal physiological circulation by releasing Cu to natural Cu-carriers. The key novelty of this approach lies in that S4N mimics the N-terminus of Aβ4-x peptide (ATCUN motif), providing 4N square planar Cu(II) coordination with high affinity and selectivity. In general, S4Ns do not act as traditional chelating agents by simply eliminating metals from the organism, on the contrary they perform as Metal–Protein Attenuating Compounds (MPACs) by redistributing and assisting in the restoration of brain biometal homeostasis. This synergistic but novel strategy will allow us to carry out a comprehensive study of the new compounds and shed light into discovering promising drug candidate. Of equally importance, TS4NC MCSA will open new research horizons and significantly boost scientific career of the applicant, by helping her to reach professional maturity during the fellowship.
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Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
SW7 2AZ LONDON
United Kingdom