Alzheimer’s disease (AD) is an age-related neurodegenerative disorder responsible for about 2 million deaths per year. Despite tremendous progress in basic research within the last years, its efficient treatment and diagnostic tools are still lacking. The previous studies have gathered sufficient evidence of a causative role of the aggregates of two proteins - amyloid beta and tau - in the AD pathogenesis. Both of these proteins can form highly toxic oligomeric species, which are the primary suspects of AD-related neurotoxicity. However, due to experimental difficulties the detailed structural and functional characterization of the oligomeric forms has been a big challenge. In the proposed project we aim to build on cutting-edge technologies and novel approaches to obtain atomic-level structures and investigate interactions of the amyloid beta and tau oligomers. Thus, this multidisciplinary project will apply (I) cell-free protein expression and purification protocols for incorporation of various selectively 13C, 15N and 19F labeled amino-acids; (II) microfluidics in order to generate size-controlled oligomers (III) solid-state NMR (ssNMR) at fast magic-angle spinning (MAS) regime tailored for 1H and 19F detection schemes. The anticipated outcome of this will be a unique combination of approaches to study amyloid aggregates, which can be further used and adapted for studying other protein assemblies. The project results will form the basis of innovation in the treatment of AD as well as other tauopathies.

The aim of Natalion is to foster innovation excellence of LIOS by the establishment of the Natural Products Research (NPR) group and implementation of the LIOS Innovation Hub as a complementary structural change. The introduction of new research strands and the structural changes will be achieved under the leadership of ERA Chair holder Dr. Stefano Donadio, an experienced Research and Innovation (R&I) professional. Project objectives: O1 Establishment of the NPR group, including its capacity build-up; O2 Setting up the research directions of the NPR group with a focus on new technologies and products; O3 Integration of activities of the NPR group into internal and external collaborative projects including 3I mobility; O4 Increase competitiveness for attraction of external research funding; O5 Establishment of the LIOS Innovation Hub and its integration into institutional, national and EU ecosystems; O6 Development of a motivating and inclusive institutional environment which fosters innovations and entrepreneurial culture; O7 Enabling institutional compliance to ERA priorities and UN Sustainable Development Goals; O8 Dissemination and exploitation of the results of the NPR group according to PEDR and a communication plan; Establishing the NPR group, the international recruitment, as well as the development of environment, fostering innovations will nurture brain circulation for researchers and innovators. The establishment of the LIOS Innovation Hub and its integration into institutional, national and EU ecosystems will deliver institutional reforms with a focus on innovation. Setting up new research directions and integrating the NPR group into internal and external collaboration networks under the competent guidance of the ERA Chair will leverage excellence of R&I and increase the competitiveness for attraction of external research funding. Better communication of R&I results to society will be achieved by Dissemination and Exploitation of the project results.

The expertise, resources and specific knowledge of all participating parties will be combined to achieve a breakthrough in design, synthesis and application of peptide analogues (peptidomimetics) possessing photo-controlled biological activities, with special emphasis on anti-microbial and anti-cancer activities. The main idea behind the Project consists in chemical incorporation of artificial photo-controllable building blocks into known biologically active peptides by replacing their natural building blocks – the amino acid residues. Such a modification would provide photocontrolled peptidomimetics which can reversibly change their structure between two different photo-forms upon irradiation with light of different wavelength. The participating parties possess general know-how for design of the peptidomimetics which can exist in two photo-forms, biologically active and inactive ones, reversibly interconvertible by light of different wavelength. This opens a possibility to convert inactive peptidomimetics to active compounds by irradiation with physiologically benign light directly in tissues with very high spatiotemporal precision and can be a fundamental basis of new therapeutic strategies. The research staff exchange and other activities planned under the Project will be dedicated to accomplish four complementary work packages: (i) carrying out pharmacokinetic and toxicity studies of the photocontrolled peptidomimetics synthesized by the parties previously; (ii) evaluation of novel photocontrolled building block chemotypes for their compatibility with peptides; (iii) creation of new photocontrolled peptidomimetics, especially based on the novel building blocks and the know-how developed by the parties (e.g. using “stapled peptides” technology); (iv) multidisciplinary training of the researchers whose future work will be aimed at further development of the most advanced photocontrolled peptidomimetics as drugs suitable for photodynamic therapy.

There is an enormous and unmet medical need to find efficient methods of prevention, diagnosis and disease- modifying therapies for neurodegenerative disorders, including Alzheimer’s disease (AD), other tauopathies and Parkinson’s disease (PD). The common molecular denominator of tauopathies are pathological forms of tau protein, and in Parkinson’s disease these are pathological forms of -synuclein. Moreover, -synuclein has a distinct role in pathophysiology of tauopathies, mainly in tau hyperphosphorylation and aggregation, and vice versa. Tau pathology relates to conformational changes during oligomerization and assembly resulting in toxicity. Given their role in the pathogenesis, conformationally altered and assembled tau or -synuclein would be a promising molecular target for disease-modifying therapies. However, the field is still lacking a deeper understanding of associated structural changes in the course of assembly and their inducers on the pathway towards pathological forms of these proteins; therefore, the pharma development is hampered. The main aim of the InterTau project is the detailed structural and biophysical characterization of tau and -synuclein -synuclein protein and their variants in monomeric, oligomeric and fibrillar states relevant for AD, other tauopathies. The InterTAU consortium is composed and academic partners with cutting- edge methodologies suitable for functional and structural characterization of the tau assembly pathway by solution and solid-state nuclear magnetic resonance (NMR), cryo-electron microscopy and cellular assays corroborated by bioinformatics. The mutual transfer of complementary expertise envisaged in the project will facilitate academic outcome and biotechnological development. Specific expertise will be transferred from three institutions in North America and one institution from Argentina. The results of InterTAU will be directly translated into innovation in biotech through the non-academic partner. The platform for sharing knowledge will be a foundation of sustainable cooperation beyond the InterTau project.