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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - SyDAD (Synaptic Dysfunction in Alzheimer Disease)

Teaser

There is an urgent need for finding novel approaches to promote drug discovery for Alzheimer Disease (AD). Despite an overwhelming increase of dementia costs and an aging population, there is currently no disease modifying therapies on the market and we are facing a large...

Summary

There is an urgent need for finding novel approaches to promote drug discovery for Alzheimer Disease (AD). Despite an overwhelming increase of dementia costs and an aging population, there is currently no disease modifying therapies on the market and we are facing a large number of failed clinical trials and the decision of pharmaceutical companies to discontinue their nervous system R&D programmes. Increased collaboration between academia, providing a huge knowledge base; and the private sector, providing the understanding of the drug discovery value chain, would provide a novel approach to find cures for dementia.
In the European Training Network “Synaptic Dysfunction in Alzheimer Disease” (SyDAD), we are meeting this need by training 15 Early Stage Researchers (ESRs) to a new generation of researchers with an innovative mind-set and full understanding of the requirements of academia, pharmaceutical companies, the clinics and the societal challenges.
The research programme focuses on synaptic dysfunction, the main connection point between pathology and cognitive decline in AD. We have collected world-leading expertise in different AD fields as well as in synaptic biology to serve as supervisors for the ESRs. In addition, we have included two pharmaceutical companies to facilitate potential future implementation of the results into clinical trials and to expose the ESRs to the private sector.
The objectives for the research programme of SyDAD are:
1. To investigate the pathways behind synaptic dysfunction in AD and thereby identify novel pharmacological targets, using state‐of‐the‐art and standardised methodology and an interdisciplinary approach.
2. To establish an efficient and collaborative drug discovery platform for intervention of AD synaptic dysfunction based on resources already present within the network as well as novel tools.
3. To test interventional strategies already in the pipe‐line within the network, or which will be identified in aim 1, with the ultimate goal of advancing to clinical trials, using the platform of aim 2.

Work performed

During the first period, many of the ESRs have dedicated a substantial amount of time on method development and characterization of animal models. These methods and models will be essential for the future progression of the project but can also in many cases be used to evaluate novel treatment strategies in our drug discovery platform. In addition, some of the animal models can give important information about the mechanisms underlying synaptic dysfunction. For example, we have elucidated the effect on synaptic composition and function in mice models where novel targets, such as RNF10, RyR2 or Cap2 have been deleted.
We have also elucidated important synaptic effects of, and species differences in, processing of the amyloid precursor protein (APP), an important player in AD pathogenesis. Importantly, we will also in the near future file a patent on a peptide that can alter APP processing in a beneficial manner and thereby rescue cognitive deficits in AD mouse models.
We are also starting to get the first results on which synaptic parameters that are affected by spreading of truncated or hyperphosphorylated tau, another main player in AD pathogenesis.
Several ESRs are also investigating the role of mitochondria, the power plants of the cells, as well as Ca2+ handling for synaptic function. A small screen for mitochondrial stabilisers has been performed and we plan to evaluate the effect of these compounds on synaptic function. Other ESRs are exploring the role of cholesterol or synapse-to-nuclear signalling or screen for novel targets using mass spectrometry.
Finally, we are also evaluating synaptic biomarkers as potential read-outs for efficacy of treatment and recently published a paper on EEG patterns as such a potential biomarker for synaptic function.

Final results

As mentioned above, we have during the first period established a number of state-of-the-art methods and models for studying synaptic dysfunction. These methods and models will enable a more thorough delineation of the synaptic dysfunction in AD. For example, super-resolution microscopy will help to assess functional and structural synaptic changes at a nanometer scale. Viral and optogenetic approaches will also facilitate the investigation of cell type specific alterations. In addition, many of the methods and models can be used for target and lead validation in the drug discovery value chain. Importantly, one of our goals are also to identify novel biomarkers for synaptic integrity and/or function for better stratification of patients and efficacy assessment in future clinical trials.
We have already identified a potential new treatment strategy that decrease the production of the toxic amyloid beta-peptide and improve cognitive function in AD mouse models. We are also performing a screen for mitochondrial stabilisers and are evaluating adenosine receptor antagonists as potential treatment strategies. Although all these compounds are in a very early phase of development, it gives hope for novel approaches to tackle the synaptic dysfunction in AD.
Due to the short time period of the project, it is unrealistic that any of our findings will be taken into clinical trials during the scope of the project. However, by a collaborative effort to carefully delineate the synaptic dysfunction, the establishment of a network of highly talented young researchers, and an establishment of a drug discovery platform, we will greatly increase the chances of an introduction of new treatment strategies for AD in the future. The need for such strategies is urgent and the socio-economic impact, as well as the relief of the patients and their relatives, would be immense. The incidence of dementia is estimated to double every 20 years and reach 130 million in 2050 and the total cost of dementia care will reach 1 trillion in 2018.