Periodic Reporting for period 2 - SyDAD (Synaptic Dysfunction in Alzheimer Disease)
Okres sprawozdawczy: 2017-11-01 do 2019-10-31
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.
The European Training Network “Synaptic Dysfunction in Alzheimer Disease” (SyDAD), have met this need by training 14 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 and an established network for future collaborative efforts.
In addition, SyDAD has greatly promoted collaborations among the SyDAD sites and several collaborative research projects have been initiated. 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 were:
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 pipeline 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.
The research performed by the ESRs has significantly increased our understanding about the pathways underlying synaptic dysfunction in AD, models and methods have been developed and biomarkers and interventional strategies have been evaluated.
Furthermore, the ESRs have been trained in advanced methodology at the Bordeaux School of Neuroscience and by utilising the expertise at different SyDAD sites during secondments. The methodological expertise has also been further spread by organising a final course open to young researchers world-wide.
A large number of scientific articles have been published whereof several involved collaborative efforts between SyDAD sites.
The European Training Network “Synaptic Dysfunction in Alzheimer Disease” (SyDAD), have met this need by training 14 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 and an established network for future collaborative efforts.
In addition, SyDAD has greatly promoted collaborations among the SyDAD sites and several collaborative research projects have been initiated. 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 were:
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 pipeline 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.
The research performed by the ESRs has significantly increased our understanding about the pathways underlying synaptic dysfunction in AD, models and methods have been developed and biomarkers and interventional strategies have been evaluated.
Furthermore, the ESRs have been trained in advanced methodology at the Bordeaux School of Neuroscience and by utilising the expertise at different SyDAD sites during secondments. The methodological expertise has also been further spread by organising a final course open to young researchers world-wide.
A large number of scientific articles have been published whereof several involved collaborative efforts between SyDAD sites.
The research programme of SyDAD has shown great progress and increased our understanding of the mechanisms underlying synaptic dysfunction in AD.
For example, we have elucidated important synaptic effects of altered processing of the amyloid precursor protein (APP), an important player in AD pathogenesis. Importantly, we have filed a patent on a peptide that can alter APP processing in a beneficial manner and thereby rescue cognitive deficits in AD mouse models. In addition, another patent for a similar peptide that affects the connection between APP processing and the cytoskeleton and morphology of the synapses, is about to be filed.
We have also developed several animal models for spreading of tau, another key player in AD, and show its connection to inflammation. A novel protein binding to tau, Yes1, has been identified and an inhibitor of tau aggregation has been evaluated as an interventional strategy.
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.
Several ESRs have also investigated the role of mitochondria, the power plants of the cells, as well as Ca2+ handling for synaptic function. A mitochondrial stabiliser which could potentially be used as an interventional strategy has been identified.
Other ESRs have been exploring the role of cholesterol or synapse-to-nuclear signalling. In addition, a number of pre-synaptic proteins have been identified to be altered in AD brain.
Finally, we are also evaluating synaptic biomarkers as potential read-outs for efficacy of treatment including quantitative EEG and measurement of synaptic proteins in CSF.
In addition to the research programme, the ESRs have been extensively trained in advanced methodology as well as transferable skills and utilised the diverse expertise of SyDAD during secondments and through collaborative research projects.
The results of SyDAD have been disseminated in a large number of publications as well as by oral and poster presentations at conferences and by outreach activities.
For example, we have elucidated important synaptic effects of altered processing of the amyloid precursor protein (APP), an important player in AD pathogenesis. Importantly, we have filed a patent on a peptide that can alter APP processing in a beneficial manner and thereby rescue cognitive deficits in AD mouse models. In addition, another patent for a similar peptide that affects the connection between APP processing and the cytoskeleton and morphology of the synapses, is about to be filed.
We have also developed several animal models for spreading of tau, another key player in AD, and show its connection to inflammation. A novel protein binding to tau, Yes1, has been identified and an inhibitor of tau aggregation has been evaluated as an interventional strategy.
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.
Several ESRs have also investigated the role of mitochondria, the power plants of the cells, as well as Ca2+ handling for synaptic function. A mitochondrial stabiliser which could potentially be used as an interventional strategy has been identified.
Other ESRs have been exploring the role of cholesterol or synapse-to-nuclear signalling. In addition, a number of pre-synaptic proteins have been identified to be altered in AD brain.
Finally, we are also evaluating synaptic biomarkers as potential read-outs for efficacy of treatment including quantitative EEG and measurement of synaptic proteins in CSF.
In addition to the research programme, the ESRs have been extensively trained in advanced methodology as well as transferable skills and utilised the diverse expertise of SyDAD during secondments and through collaborative research projects.
The results of SyDAD have been disseminated in a large number of publications as well as by oral and poster presentations at conferences and by outreach activities.
By a collaborative effort to carefully delineate the synaptic dysfunction, the establishment of a network of highly talented young researchers as well as the development of novel disease models, biomarkers and interventional strategies, SyDAD had significantly contributed to 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 have now reached 1 trillion Euro.
A number of state-of-the-art methods and models for studying synaptic dysfunction have been established which will further enable a more thorough delineation of the synaptic dysfunction in AD. Many of the methods and models can be used for target and lead validation in the drug discovery value chain. Importantly, we have also investigated translational biomarkers for synaptic integrity and/or function for better stratification of patients and efficacy assessment in future clinical trials. Finally, 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. In addition, a compound that stabilises mitochondria has been identified. 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.
A number of state-of-the-art methods and models for studying synaptic dysfunction have been established which will further enable a more thorough delineation of the synaptic dysfunction in AD. Many of the methods and models can be used for target and lead validation in the drug discovery value chain. Importantly, we have also investigated translational biomarkers for synaptic integrity and/or function for better stratification of patients and efficacy assessment in future clinical trials. Finally, 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. In addition, a compound that stabilises mitochondria has been identified. 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.