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Final Report Summary - NANONEUROPROTECTION (Nanomaterials for treatment of neurodegenerative disorders)

Our project combines advanced methods of neurobiology and nanoscience to (1) characterize novel therapeutic targets and neuroprotective pathways in the brain and (2) design efficient protectants against neurodegenerative conditions focusing on the novel neuroprotective protein S100A4 and its peptide derivatives that we have recently identified. The organization of the programme is modular and based on four work packages (WP).
WP1. Effect of S100A4 and its derivatives in cell models of neurodegeneration.
WP2. Clarification of mechanisms of S100 neuroprotection
WP3. Fabrication and optimization of S100-based neuroprotectants
WP4. Management/Internal review.

Main results:
WP1:We have tested the parent protein (S100A4) and its peptide derivatives, H3 and H6 (Fig 1), in clinically relevant cell models of stroke and Parkinson's disease (PD). Hippocampal, midbrain or immortalized dopaminergic neurons were subjected to oxidative stress, a major contributor to neuronal injury in stroke, or to an endogenous toxin for the PD initiation, reproducing the key hallmarks of the disease. We found that S100A4, H3 and H6 all had robust neuroprotective effect in these models and also induced neurite extension from primary and immortalized neurons (Fig 2).
Furthermore, we have shown that H3 and H6 specifically mimic neuroprotection by S100A4 in vitro,but not its non-neuronal effects such as stimulation of cell migration/proliferation, thus making the two peptides suitable for further development as specific drugs for treatment of neurological diseases.
WP2:We have identified a novel mechanism of neuroprotection byS100A4 which involves signaling through ErbB, important neuronal receptors implicated in pathologies such as epilepsy, schizophrenia, Alzheimer’s and Parkinson’s diseases. To this end, we have employed several neurotoxicity models in cultured neurons including direct oxidative stress, the injury contributing to many brain insults, and excitotoxicity, in which neuronal death was evoked by kainate, a toxic agent inducing neuropathology characteristic for human temporal lobe epilepsy. We have also demonstrated that S100A4 directly binds to ErbB and activates pro-survival messengers such as Akt in the ErbB-dependent manner. Finally, using rodent models we demonstrated that expression of S100A4 and ErbB are correlated in brain injury.
WP3:We have produced a range of spherical gold nanoparticles (AuNP) with varying sizes functionalized with monomeric S100 peptides. We have also engineered and functionalized a novel class of AuNPs, gold plasmonic nanostars (AuNS, Fig 3), whose physicochemical properties potentially offer several advantages over regularly shaped NPs in the sensing and therapeutic applications. The multispiked morphology of nanostars provides an easy access to target molecules on cell membranes and a large supporting surface to which neuroactive agents and sensors can adsorb. AuNS were further functionalized with polyethilenglycol (PEG) and, as demonstrated by our pilot data, are capable to cross the blood-brain barrier. AuNS had no adverse effects on neuronal viability, and the H3-and, to a lesser extent, H6-functionalized AuNS had trophic effects in cultured neurons justifying their further development for neuroprotectant design. We have also synthesised a PLGA NP platform for delivery of the S100 neuroprotectants. The PLGA can be filled with MRI active compounds such as iron oxide for combined imaging and therapy.
WP4: We set up quarterly meetings to evaluate research progress, address methodological aspects of neurobiological experiments and nanoparticle synthesis, and to evaluate status of training achieved based upon task put forward

Conclusions: We have characterized a novel signalling cascade which linksthe neuroprotective protein S100A4 with ErbB receptors revealing a novel mechanism of neuroregeneration in brain pathologies. We have also shown that S100A4 and its peptide derivatives protect neurons in several models of neurodegeneration (stroke, epilepsy, and Parkinson's) and fabricated S100-functionalized nanoparticles which proved neurotrophic in cultured neurons making S100A4 mimetics attractive candidates for further development as neuroprotectants.The manuscript based on research data from WP1 and WP2 with the Fellow as a leading author is currently under submission.

Potential impact
We have proven that the S100-ErbB axis is involved in multiple aspects of neuroprotection thus representing a novel pro-survival pathway in the brain, demonstrated efficacy of S100-derived peptides in cell models of neurodegeneration, and engineered neurotrophic S100-targeted nanoparticles which can be further developed as a platform for drug design. Our results will enhance understanding of mechanisms of neurodegeneration at a fundamental level and potentially offer safe producible compounds which can be used for treatment of neurodegenerative diseases and thus have wide socioeconomic implications, given that in 1990-2010, mortality attributed to these diseases doubled, and years lived with the related disabilities increased by >50 currently costing the EU €65 billion a year in care.These aims also perfectly fit with the objectives of the EU Joint Programme - Neurodegenerative Disease Research “to rapidly enhance our understanding of the causes of neurodegenerative diseases resulting in better medical and social care systems”.

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