Researchers on the NAB3 project, which is supported by JPND, are working toward more precise in vitro models of the blood-brain barrier under Alzheimer’s conditions
A lack of representative models One of the major challenges in the development of new diagnostic tools and therapeutic approaches for Alzheimer’s disease is the successful passage of drugs across the blood-brain barrier, a membrane that acts as a natural defense system to keep potential toxins in the bloodstream from entering the central nervous system.
Researchers conducting pre-clinical trials on Alzheimer’s drugs rely on in vitro models of the blood-brain barrier that simulate disease conditions. However, existing models of the blood-brain barrier do not yet reflect the specific changes seen in the blood-brain barrier of people with Alzheimer’s disease.
Enter NAB3 For Francesca Re, a biochemist at the University of Milano-Bicocca, it was clear that the introduction of in vitro models of the blood-brain barrier in Alzheimer’s-specific conditions had the potential to accelerate new findings. In 2015, when JPND launched its JPco-fuND call together with the European Commission, she and her collaborators applied for a JPco-fuND grant to try to bring this new model to fruition. The application was successful: their consortium, NAB3, was one of 21 projects selected for support.
Launched at the start of 2016, the three-year project aims to combine different cellular types and organotypic brain slices or neuronal cultures to achieve an in vitro model of the human blood-brain barrier in the Alzheimer’s disease state. “The whole NAB3 team is really excited about the development of this model,” Re said. “It’s a critical next step and will represent an innovative and highly valuable new tool for drug design and testing that we hope to be able to make available to other researchers in academic labs and pharmaceutical companies.”
A coordinated European effort With partners based in five European countries – France, Germany, Italy, the Netherlands and Portugal – the NAB3 project brings together expertise from across the continent and in a range of different fields, including genetic engineering, physiology, neurobiology, neuroanatomy and biochemistry. “In my opinion, the most promising advances in the Alzheimer’s field come as a result of international collaboration,” Re said. “The multidisciplinary research synergies built into the NAB3 project offer an unprecedented opportunity to make rapid and meaningful progress in the fight against Alzheimer’s disease.”
Each lab participating in the project contributes different but complementary knowledge and skills to the effort, and Re is optimistic that by working together and with persistence, NAB3 will succeed. “Each challenge offers us the opportunity to take a step forward, because every problem has a solution,” she said. “As my mentors have shown me, the key is to never give up.”
World Young Leaders in Dementia (WYLD), a network for emerging leaders in the field, grew out of the legacy meetings that followed the 2013 G8 (now G7) dementia summit: Together with JPND, the UK Science & Innovation Network identified young leaders to convene to draft a set of proposals and present them at the WHO’s First Ministerial Conference on Global Action Against Dementia in March 2015. This process sparked a number of new research collaborations and indeed the creation of the WYLD network itself.
Now with more than 130 members across six continents, WYLD is mobilising to drive forward creative new solutions for people with dementia, their caregivers, and their communities. JPND spoke with Laura Booi, William Hu, Anja Leist, Kristine Newman, and Clare Walton from the WYLD Steering Committee to learn more about what the group wants to accomplish and how they plan to do it.
Accelerating solutions to tackle dementia To help lay the groundwork for the future of dementia care, cure, research, and advocacy, the members of WYLD are working to foster new, interdisciplinary collaborations among the next generation of leaders. “WYLD members come from the broad fields of basic, clinical, health, social and care,” said Anja Leist, a research associate at the PEARL Institute for Research on Socio-Economic Inequality at the University of Luxembourg. “Most members, however, are not only researchers,” added Kristine Newman, an assistant professor at the Daphne Cockwell School of Nursing at Ryerson University. “They’re also advocates and, in many cases, care providers.”
The young leaders aim to identify ethical and daring models of inquiry and then translate them across disciplinary and national borders. Their end goal: to advance new dementia strategies that incorporate the latest innovations in technology and methods and that are global in scope. “We want to develop compelling strategies that meet the needs of a rapidly changing world,” said William Hu, Assistant Professor of Neurology and Director of the Neurodegenerative Biomarkers Laboratory at Emory University. “Dementia is a global challenge and it will require global solutions.” Hu himself has promoted scientific exchange by establishing new collaborations with young clinicians and scientists from Bulgaria, Italy, the Netherlands, Taiwan, and the U.S.
European young leaders meeting, London, February 2015
A new take from the ‘Think different’ generation According to the young leaders, many of whom qualify as so-called millennials (those born roughly between the years 1982-2000), theirs is a generation marked by a rejection of conformity and a confidence in thinking outside the box. It’s this ethos that the young leaders say allows them to bring creative brainstorming, fresh perspectives, and novel solutions to the dementia field. In short: this is a group of young people who aren’t afraid to put forward challenging new ideas.
First WHO Ministerial Conference on Global Action Against Dementia, Geneva, March 2015
As the first generation of dementia researchers who grew up with home computers, the young leaders also bring technological fluency to the field. One advantage of being a digital native, they say, is that they’re able to utilise, uncover, and recommend the most advanced tools, trends, and technologies, such as content management systems and social media, for dementia-related initiatives. For this reason, WYLD incorporates a technology and dementia element into each international workshop.
Ready, set, assume the mantle WYLD’s ongoing activities include regular meetings at international dementia conferences and participation in the World Dementia Council, with one young leader contributing to each of the five Global Teams (Research, Open Science & Data, Care, Integrated Development, Risk Reduction, and Finance). In order to develop into a truly international network, the young leaders are taking steps to implement their governance structures, formalise their communication channels and create a membership directory to facilitate connecting from both within and outside of the network. “We want to rapidly ramp up our collaborations,” said Laura Booi, Doctoral Candidate in Gerontology at Simon Fraser University in Vancouver, Canada. “That’s how we believe that we can most quickly make progress toward a world that cares for and values people with dementia.”
Japanese young leaders meeting, Tokyo, November 2014
“JPND is a clear window of opportunity to participate in an exercise to do global research to address neurodegeneration. Of course, it is up to the participating countries to shape this issue in a better fashion. We are now jumping from not just being a European but a global player, and this is a good opportunity for Europe to translate the knowledge into better clinical practice and better economies in Europe.”
What is the general perception of JPND in Spain? It is rather positive – maybe JPND is ‘half-way’ there to ultimate success, as there are still questions pending. One is the alignment of national and EU programmes, and the second is better participation of industry in performing neurodegenerative disease research. The third is more and better research and transfer of knowledge in health and social services. But overall there is a positive approach to JPND.
How are Spanish researchers performing in JPND initiatives? Our perception is that they are doing rather well if you take into account the level of commitment of research funds, the relative size of our research community in neurodegenerative diseases, and the relevance of the call topics to date, some of which are better suited to our researchers than others.
Are there initiatives in Spain for supporting researchers willing to apply for JPND funding? Although there are no specific initiatives assigned to JPND, there are more general initiatives that can serve the purpose of fostering participation of Spanish researchers in JPND. For example, the CIBER virtual research centers and the Health Research Institutes, certified according to RD 339/2004, receive funds that enable them to foster this type of participation.
What do you think is the main benefit for your country for participating in JPND? The main benefits come from putting together Spanish researchers and the Ministerial research capacities and to linking to and engaging with the research capacities in the other countries participating in JPND. This is what makes the difference!
And the ISCIII? Are there benefits to being a member of the JPND Management Board? From the ISCIII perspective, there are benefits because ISCIII is entitled to shape and fund National Health System research capacities in Spain. It is also a good window of opportunity to form a bridge between JPND and the national programmes, and also the Programme Committee delegates in Horizon 2020 in the different EU societal challenges.
Researchers from across Europe team up to decode the interplay between genetics and environment
For scientists studying the origins and pathways of Alzheimer’s disease, experimental animal and cell models are a critical tool. These models mimic the processes thought to be at play in human patients and allow researchers to assess possible treatments before moving into clinical trials. Yet most models of Alzheimer’s disease are unable to take into account the complex genetic and environmental factors involved in what’s known as late-onset ‘sporadic’ Alzheimer’s disease, which is the most common type of the disease.
An international research collaboration called DACAPO-AD is trying to change this. Led by Gabor Petzold, a professor at the German Center for Neurodegenerative Diseases (DZNE), DACAPO-AD (short for ‘Deciphering Interactions of Acquired Risk Factors and ApoE-mediated Pathways in Alzheimer’s Disease’), aims to elucidate the complex interactions between known genetic and environmental risk factors, with the goal of establishing the reliable new models of Alzheimer’s disease that scientists need to identify potential treatments.
At the intersection of genetics and environment Researchers classify Alzheimer’s disease in different groups according to the age at onset. Early-onset inherited (or ‘familial’) Alzheimer’s disease is very rare, but half of the cases have a genetic cause that is relatively well understood. Then there’s what is known as late-onset sporadic Alzheimer’s disease. This type is far more common — accounting for more than 98% of cases — but the pathways leading to sporadic Alzheimer’s disease are much less well understood and look far more complex. The most important known genetic risk factor for sporadic Alzheimer’s disease is a gene called APOE-ε4, although not everyone with sporadic Alzheimer’s disease carries the gene, and some people who do carry the APOE-ε4 gene ultimately die without ever developing Alzheimer’s disease. Indeed, around a third of sporadic Alzheimer’s patients are APOE-ε4 -negative.
For the DACAPO-AD project, the challenge is to better understand the reasons for this heterogeneity, and the researchers are focusing on the role of environmental (or ‘acquired’) risk factors. They’re trying to uncover how a range of these different factors — such as a high-fat diet, cardiovascular disease, traumatic brain injury, systemic inflammation and sleep problems — interact with the APOE-ε4 gene to result in an increased risk of Alzheimer’s disease. “It would be a real breakthrough in the field if we could understand, on a cellular or molecular level, how these risk factors trigger the onset and contribute to the progression of sporadic Alzheimer’s disease,” Petzold explained from his lab in Bonn, Germany. “Our hope is that this research will ultimately lead to better preventive strategies and novel treatment options.”
Pooling resources to speed up discovery The high-level skills and technologies needed to approach these questions meant that international collaboration was not just beneficial but necessary. DACAPO-AD, which was selected for support in the 2015 JPco-fuND call, brings together research teams from four countries: in addition to Germany, researchers in Denmark, France and Sweden are bringing different expertise to the project. “We are a team of five labs from four different countries that are sharing technologies and data to more rapidly address the same common goals,” Petzold said. The project partners were selectively identified to ensure that the combination of each lab’s unique skill set would enable the collaborators to work on questions that the individual labs wouldn’t have been able to take on alone. Moreover, all of the partners have agreed to share preliminary findings and technological developments freely within the team, with one of the consortium’s explicit goals being knowledge transfer. “We will give young researchers from each lab the possibility to travel to partner labs, Petzold explained. “This will allow our teams to learn new techniques, exchange data and get to know other researchers.”
Calling young researchers! The Alzheimer’s field is quickly evolving and offers scientists and clinicians a host of exciting challenges. To early-career researchers who are considering specializing in Alzheimer’s disease, Petzold recommends surveying a broad range of researchers, including PIs and postdocs as well as students, to see what they think the most pressing questions are facing the field and where it’s headed. “In other words,” he explained, “what novel research finding would be a real breakthrough, and how do we get there?” He advises joining a lab with a hands-on PI who has the technological and financial resources to tackle these big questions. From there, a mix of perseverance and openness, he says, is most likely to yield success: “It’s important be diligent and work hard, but also to stay flexible for new research avenues and technologies that may emerge in the future.”
By analyzing brainstem tissue and testing their findings in ongoing aging cohorts, EPI-AD, a JPND-supported project run by a young PI from the Netherlands, aims to uncover the stress-related epigenetic mechanisms linked to Alzheimer’s disease.
A few years ago, Daniel van den Hove, a neurobiologist who has long been interested in studying the connections between stress and brain function, began to think about a new question: what if stress associated with disorders such as anxiety and depression was causally linked to Alzheimer’s disease?
“We already have some evidence that a history of depression may speed up cognitive decline related to Alzheimer’s disease,” van den Hove explained from his office at Maastricht University in the Netherlands, where he is an Assistant Professor in the Department of Neuroscience. “What we want to do now is to look at the brainstem, where the regions critically involved in stress regulation and affected by depression are also affected early in Alzheimer’s disease, and see if we find any causality.”
This is the question that van den Hove and his colleagues from across Europe will explore in a new project supported by the EU Joint Programme for Neurodegenerative Disease Research (JPND). The consortium, called EPI-AD (short for “Targeting epigenetic dysregulation in the brainstem in Alzheimer’s disease”), brings together research teams from five countries: in addition to the Netherlands, researchers from Germany, Luxembourg, Spain, and the United Kingdom will collaborate on EPI-AD. The project was selected for support under the 2015 JPco-fuND call, which was co-funded with the European Commission under Horizon2020. Zeroing in on the brainstem Although EPI-AD won’t officially launch until July 2016, the research teams have spent the last several months planning via email, and they held their first face-to-face meeting in March. “I think we’re all really excited to get started on this project, which we believe represents an important shift in research focus,” van den Hove says. Although much of Alzheimer’s disease research is currently concentrated on brain regions like the hippocampus, which is affected in the later stages of the disease, van den Hove and his colleagues are looking somewhere else: the brainstem. “We suspect that the changes seen in the hippocampus are more likely to be the consequence of what’s already happened than causally involved,” van den Hove explains. “We want to shift our focus to the earlier stages — we’re looking for causal factors — and we think the best places to look are the the locus coeruleus and the dorsal raphe nucleus in the brainstem, which is where these early changes are seen.”
EPI-AD researchers will have a rich collection of tools at their disposal, starting with unique, well-defined brain tissue samples for patients and controls. The samples are banked an average of 2.8 hours postmortem, and subjects were followed for eight years on average, offering the researchers a trove of valuable new information. In addition, they’ll have access to three ongoing aging cohorts in the Netherlands and Germany, which will allow the researchers to immediately test what they find in the brain to see whether it has any predictive value in living subjects. In parallel, they will be able to directly compare their findings with other biomarkers – they’ll have access to imaging data and amyloid beta and tau as well as cognitive data – resulting in a multi-level and multi-disciplinary project. Finally, the Spanish partner, led by Manel Esteller and Raul Delgado at the Bellvitge Biomedical Research Institute, will manipulate the identified genes in stem cells of Alzheimer’s disease patients to see if they’re changed in terms of structure and function. The key question: Can these cells be made ‘healthier’ by intervening in epigenetic processes? “We’re combining a lot of recently developed knowledge in different fields and integrating it into one concept,” van den Hove says. “But what’s the use of finding something very interesting and then stopping there? Our goal is to uncover critical findings and then find a way to add value by translating this new knowledge as efficiently as possible to the clinic.”
If at first you don’t succeed, try, try again
Dr. Daniel van den Hove
For van den Hove, the path to the JPND grant wasn’t necessarily quick or easy. “When I came up with this hypothesis I was incredibly enthusiastic — I thought that this might mean something, that I could really make a difference, even in a relatively short period of time,” he explained. But his first grant application was turned down. Then another one was declined, although the scientific excellence of the project proposal was underscored by all of the reviewers. One of his mentors, Professor Klaus-Peter Lesch, urged him to be persistent. “Fail better next time,” he kept telling him. “When I saw the JPND grant opportunity, we’d already been fine-tuning this concept, working on extending our network a little more and thinking about the most interesting angles, so we were ready to apply,” he said. Ultimately, the researchers’ persistence paid off. “It’s important to keep believing in your ideas and never give up,” van den Hove says. “It’s also important as a young researcher to find mentors who will assist you in navigating the grant application process and who will help you seize new opportunities. At 37, I’m still relatively young to coordinate such a large project, but I’m lucky in that my mentors encouraged me to step forward and apply for this grant. My mentors’ support, on matters small and large, has helped me enormously, and I hope I can now more and more fulfill such a supportive mentoring role. Of course, science, in all its aspects, should never be seen as an individual effort, although many funding schemes are aimed at the individual.”
Joining forces to accelerate research progress Research collaborations that developed as EPI-AD came together have been amplified and extended since the project was selected for the JPND grant, with the partners securing funding from other outside sources to hire additional students to work on the project. “What’s wonderful about getting this grant is not just the money the grant brings in but the extra opportunities it brings along with it,” van den Hove says, explaining that over the lifecycle of the project he and his partners hope to apply for more funding and continue to expand their research collaboration. “Since a single lab can’t be experts in everything, international collaboration helps us bring together the broad range of expertise we need to make real strides in this area of research,” he says. “At the same time, as we send students and researchers back and forth between labs, we’re able to bring new knowledge and expertise from one country to another and integrate this new expertise into our own labs as well. So we aren’t just making use of each other’s expertise. We’re also bringing new knowledge back home.”
The project is expected to span three years, but the researchers expect the new information they gather could give them enough material to work with for many more. “EPI-AD gives us the infrastructure we need to generate an enormous quantity of data,” van den Hove says. “What we can do with that in the years to come is almost endless — and incredibly exciting.”
“I would be a bit sad if JPND only focused on projects with 3-5 countries involved. In these projects the researchers continue in the same way as they did before, and they do not experience these cultural influences from different specialists and you would not get this circular effectthat can spread around to all the countries. So I say to JPND that you should support projects that involve as many of the participating countries as possible.”
What impact do you think JPND is having? At the start I was not so sure about JPND because I felt it was more of a top-down idea where it is decided more-or-less from the Management Board what areas should be focused on, with the input of the Scientific Advisory Board. I was afraid that the research councils and funding organisations in each country would reduce their interest. Now, I can only give the example from my own country, Sweden, but I can say that they have been extremely positive to JPND, and they have put in extra funds, in addition to the support that already existed. This extra addition of funding is due to JPND, and I am sure that this is the case in most other countries. Globally, I think there is growing interest worldwide in JPND – we can see the collaborations starting with Canada, with interest also now coming from Asia and America.
What do you think are the most pressing issue in this area of research? This is a field that is really evolving. From a societal perspective, disorders like Alzheimer’s, Parkinson’s and Vascular dementia are very common and are a high cost to society. That means in the future, with aging populations, greater efforts are required to stimulate research, and to simulate clinical work with these patients. Due to the increasing demand, and increasing age of populations, if we don’t do anything in research, there will be a collapse of our healthcare systems. So we need to focus not only on diagnostic processes, but we need to also develop new pharmacological treatment strategies for these patients.
What is the general feeling you get from researchers in this field? There are different views from different categories of people. If you look from the GP/Doctor perspective, I can see that GPs are rather nihilistic. They have not yet seen any great success from the new drugs that are really the first-generation of pharmacological treatments in this area, so they may be a bit negative. However, from a society perspective we are forming teams of carers for community care. With more research these teams are really increasing their knowledge, and that gives back very positive feelings. From the specialist clinicians I think it is noticed that Nobel prizes are regularly given out in this field (e.g. prion-like properties, signalling systems in the brain, MRI and PET, new microscopes to study the interaction of neurons + chemical substances in the brain). It is a fascinating research area, and an area that is more and more recognised.
What would your advice be to younger researchers? For young people who want to come into research, the brain is fascinating. The explosion in molecular biology, cell biology, genetic findings combined with the technological advancements seen now with MRI, functional imaging, positron emission tomography are very exciting for brain research. So even if we are not solving the ultimate question in the short term, we will see great progress through these new technologies coming into this field. I really want to combine fundamental knowledge about the diseases with technology and biochemical research, and to also give young people future possibilities not only for a clinical or academic career, but also to work with industry in the future. It is not only important for them but also for Europe. Europe has many strengths – we have good clinical work, good pre-clinical work, but have lost part of the industry. If we could really integrate these three, we would play a stronger part in developing new drugs and developing ideas within Europe.
“The challenge is global, so the action must be global – yours and mine!”
What is the general perception of JPND in Slovenia? Of the many initiatives of which I am aware, JPND is probably the most well-perceived and, from the organisational point-of-view, the most advanced. The idea of JPND is very nicely perceived within both the political and research spheres, and also from the clinical perspective. This is probably one of the reasons why, in 2015, Slovenia is hosting three major events associated with Dementia – Alzheimer Europe, the European Alzheimer’s Disease Consortium, and a Vascular Dementia conference – all of these events were somehow facilitated by JPND being part of the new Slovenian philosophy on neurodegeneration.
How are Slovenian researchers performing in JPND initiatives? Slovenian researchers were part of the first call (2011) – where we participated in two consortia – BIOMARKAPD and DEMTEST, and both of these have facilitated networking and increased the level of standards among Slovenian scientists. It is interesting that although the recent recession has reduced the amount of money available for research, the researchers themselves wrote a letter to the Ministry asking them to support the JPND initiatives.
Are there initiatives in Slovenia for supporting researchers willing to apply for JPND funding? There were very energetic initiatives when JPND was established and when the first call was launched in 2011. However, due to the recent recession and global financial crisis, this support has been more verbal than actual. However, the Directorate for Science at the Ministry of Education, Science and Sport is striving to get funding for the JPND calls in 2016. It is also very good that recently the Ministry of Health expressed an interest in JPND, particularly in more clinically-oriented studies and also in palliative care, so we have now their verbal promise that they will join the boat.
What do you think is the main benefit for your country for participating in JPND? For Slovenia, as a small country of 2 million people, the consequences of the first call were very, very great for Slovenia. It not only advanced our neuroscience but, importantly, it allowed us to conduct extensive networking at the time of the first call. Probably JPND is the reason why we are one of the rare successful countries to apply for the TEAMING project, and we are in the first phase. We are also more successful in applying for international calls – one of our successes is a project in which, together with Norwegian colleagues, we are trying to establish a dementia-friendly city in one of the smaller cities – Telja. Additionally, through the JPND initiative to identify young leaders or ambassadors of dementia, we founded a group of several of them and in fact two of them had a very active role in the G7 London JPND meeting and also the WHO Ministerial meeting in Geneva.
And your Ministry? Are there benefits to being a member of the JPND Management Board? Certainly. As a rather small, newly-emerged country, it is very important for our scientists as well as our politicians to make the right priorities, based on the right values. Being a part of a larger group of scientists as well as politicians certainly helps that we are making the right choices. So being part of the MB of JPND is very important, particularly because of its philosophy, as scientist/clinicians are forced to sit with their colleagues from the Ministry, so the decision is logical and economically sound.
Dr. Charlotte Teunissen of the VU University Medical Center in Amsterdam was a work package leader for BIOMARKAPD, a JPND project on biomarkers for Alzheimer’s disease and Parkinson’s disease that ran from 2012-2015.
In an interview with JPND, she reflects on the project and discusses the importance of biomarkers for research into neurodegenerative diseases: