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SYSPHARMAD Report Summary

Project ID: 614944
Funded under: FP7-IDEAS-ERC
Country: Spain

Mid-Term Report Summary - SYSPHARMAD (A systems pharmacology approach to the discovery of novel therapeutics in Alzheimer´s disease)

The objective of the SysPharmAD project is to identify novel biomarker signatures in Alzheimer´s disease that correlate with clinical outcomes, and discover combinations of potential drug targets and chemical probes able to modify the biology of the disease. This would provide the bases to effectively monitor the onset and progression of the pathology from very early (asymptomatic) phases and the response of the system to the modulation of the protein nodes selected.

In the proposal, the main objective was dissected into three intermediate goals, that also correspond to the different WPs and tasks: i) Elucidation of the molecular changes that occur in the hippocampus during the onset and progression of AD ii) Construction and modeling of the AD associated network and iii) Identification and validation of early markers in AD and combinations of chemical probes able to modify the biology of the disease. Please, find below a brief description of the status and progress made in each of the WPs.

WP1: Molecular monitoring of AD progression.

The objective of this first WP is the elaboration of full molecular profiles of AD progression in animal models, and to investigate whether we could correlate them with the cognitive impairment shown by the animals. The original proposal only contemplated the use of one animal model, namely the 3xTg-AD, overexpressing human APP and mutated PSEN1 and TAU. However, and following the advise given by the grant Reviewers, we decided to include extra models of very different nature such as two APP knock-in models (i.e. NL-F, and the more aggressive NL-G-F) including some well defined mutations of familiar AD. The inclusion of these two extra models will, indeed, increase the significance and robustness of our findings.

As of today, we have finished with all behavior tests (i.e. Morris water maze, Y-maze and object recognition) for the three animal models at different ages, representing the different stages of Alzheimer´s disease. We have also extracted and prepared all the hippocampal samples for high-throughput molecular profiling. Of these, we have full RNAseq and proteomics results for the 3xTg-AD mice, while the samples from the two knock-in models are currently being processed. We expect to have the full molecular profiles for the three models by the end of January 2017. In addition, we have also finished the in situ hybridizations to quantify the Ab plaques/oligomers and TAU tangles in the hippocampus and cortex of all the animals, finding some interesting correlations with the cognitive impairments shown by each animal.

Overall, this first WP is 95% complete.

WP2: Data integration and network modeling.

The objectives of this WP are the construction of AD-associated networks, including individual AD-motifs, and the development of a dynamic framework to monitor the disease progression. The first objective has been fully achieved, since we have identified five physio-pathological motifs related to AD (e.g. amyloid pathology, TAU pathology, oxidative stress, neuronal death and environmental factors) and characterized the key gens and proteins associated to each of these motifs. We have also built the protein interaction network connecting all the proteins involved in the mentioned AD-motifs, using the most updated versions of the human interactome. In fact, last year we started a collaboration with several US and Canadian groups that are charting the Human Reference Interactome (HuRI), which has granted us access to the data as it is being generated. Finally, we have already mapped the molecular changes occurring at each disease stage (as charted in the 3xTg-AD model) in the AD-related network, so that we know what are the processes affected at each stage.

As for the AD progression modeling, we have already implemented a novel computational framework to propagate perturbations in a given set of network nodes (i.e. proteins) and to evaluate their global effect on the system. However, we have not yet applied our methodology to AD, since we are waiting to have the complete molecular profiles for the three mice models used in the project, so that we can readily compare results and disease progression mechanisms.

Overall, the completion of this WP is 70%.

WP3: Identification and validation of AD biomarkers and novel therapeutic strategies

Obviously, this is the less complete WP of the project. However, we have made important progress in different fronts. On the one hand, we have been developing and validating novel network-based strategies to tackle complex diseases. Although we have not tested them in AD yet, our approaches yielded very interesting results in the identification of synergistic drug combinations to tackle breast cancer. There is however an important difference between breast cancer and AD, and this is that we want to kill cancer cell, while we want to revert a disease state into a healthy one in AD. This represents important changes in the way we evaluate the global impact of drug perturbations, but we are already working on it and hope to have the first results, ready to be validated, by spring 2017. In addition, we have also developed, implemented and validated chemo-centric models to identify drug reprofiling opportunities in several complex diseases, including AD.

On the other hand, we have developed a panel of cell models to test the capacity of drug-like molecules and chemical probes to modify the biology of AD. In particular, we have used CRIPSR/Cas9 to introduce APP, PSEN1 and TAU AD-related mutations in 2D and 3D cultures of SH-SY5Y cells, showing that they are an excellent first-line choice to perform drug screens in AD.

Overall, this the tasks in WP3 are 25% complete.

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