WELCOME TO THE VIB-KU LEUVEN CENTER FOR BRAIN & DISEASE RESEARCH UNDERSTANDING THE BRAIN, CURING DISEASE
Our director and vice-director, Patrik Verstreken & Joris de Wit, together with our director of administration Hilde Govaert FIVE COMMON THEMES UNITE OUR RESEARCH Our research spans a diverse set of topics, from neuronal development to neurodegeneration; from health to disease 4 MORE THAN A DOZEN RESEARCH TEAMS Meet our group leaders and explore their research focus 6 We host two visiting PIs 10 Our extraordinary research community 11 EXPLORE OUR SCIENCE We study the mechanisms of pain research 12 We study what causes neurodegenerative disease 13 We study protein aggregation 14 We study disease mechanisms 16 We develop new methods and models 17 We develop new research tools 18 We develop new resources 20 MEET OUR EXPERTS Our dedicated experts are at your service to push your research forward 22 MAKING AN IMPACT We aim to make an impact for patients and for society A hub for research talent At the Center for Brain & Disease Research we believe that understanding how our brain is shaped to control thought and behavior—and how it loses these abilities in disease—is one of the most urgent and pressing challenges of this century. It is a valiant goal, but our teams are making immense progress taking multidisciplinary approaches to unlock the secrets of the brain and mind. To achieve our goals, we invite the best minds to pursue their ideas with us. Diverse talents, who share their expertise, creativity and drive. If you share our mission, please refer to the ample opportunities, or reach out spontaneously to one of our groups. We explore how the brain develops, ages and performs, we study its remarkable resilience but also how it falls to dementia, psychiatric disability and movement disorders. Our different research groups are bridging disciplines, from artificial intelligence, microelectronics and nanoscience, to microfluidics, single cell analysis and chimeric animal models. The journey doesn’t stop there. Through partnerships across the globe, we disseminate our ideas and our findings, securing important new investments. Located at Europe’s number one innovative university, KU Leuven, our Center is among the most exciting locations worldwide to pursue original ideas. We have created a biotech ecosystem including several new startups and millions in investments in the past few years. This shows that the strongest basic science propels discovery and innovation. 26 Explore the recent success story of Muna Tx Understanding the brain, curing disease 27 MEET OUR ALUMNI Three of our alumni reflect back on their time at our Center, and how it has shaped their career We work hard every day to create a collaborative and inclusive environment, where everyone can bring their best ideas and work to the table. Through excellent research facilities, and by offering a wide array of opportunities for training and professional development, both research and researchers thrive. When communities come together, extraordinary things are possible. While the past years have been challenging, flexibility, resilience and broad care and support have been the differentiating factors in our day-to-day activities, not only in our labs, but also in our expertise units. 28 LEUVEN, BELGIUM Our hometown has a rich history and perhaps an even richer future. Home to one of the oldest universities in Europe (and to Stella Artois), it has been consistently recognized as one of the most innovative and open-minded cities in Europe. We look forward to what's in store for the next months and years. Patrik Verstreken, Hilde Govaert & Joris de Wit Explore all opportunities at jobs.cbd.vib.be 3
OUR RESEARCH QUESTIONS NEURONAL AND NEURODEGENERATIVE DISEASE Tracking memories in the Drosophila brain (Joana Dopp, Liu lab) The power of plants SYNAPSES, CONNECTIONS AND BEHAVIOR We explore new molecular mechanisms in the context of Alzheimer’s disease, Parkinson’s disease, ALS, frontotemporal dementia, but also autism, epilepsy and intellectual disability. Together with our tech transfer team, we translate our findings into therapeutic avenues. The brain poses specific challenges for drug delivery as it is shielded by a blood-brain barrier. That is why we are also developing innovative tools to ensure that drugs for brain diseases can effectively reach their target. We elucidate how trillions of synaptic connections are established and what determines their specificity, stability, plasticity and function. How does glial support play its crucial role? How does sensory input regulate behavioral output? What is the role of sleep? How can we correct synaptic defects that result in disease? We also exploit our knowledge of brain wiring to create induced human neuronal circuits on purpose designed multielectrode arrays, even in 3D, allowing us to study how neuronal computation is affected in human (neurodegenerative) disease. BRAIN DEVELOPMENT AND REPAIR We study the developmental processes that define brain size and glial and neuronal identity. We look for human-specific processes that have resulted in the unique cognitive abilities of our species, from the fundamentals of cell-type specificity, to delineating the code of neuronal wiring and the formation of synapses. By differentiating and transplantating human brain cells, we aim to develop better models for human brain disease, and ultimately, to explore the possibility of brain repair. TOXIC PROTEIN ASSEMBLIES The biophysical properties of certain proteins allow them to sometimes separate in droplets in the cytoplasm (phase separation) or even aggregate in an insoluble mass. We study how such protein assemblies form, and what the functional consequences are. Some of our scientists are flipping things around and exploit the fact that many proteins have the intrinsic propensity to aggregate: they developed the technology to induce protein aggregation in ‘unwanted cells’, such as antibiotic-resistant bacteria or cancer cells, to induce their death. THE BRAIN AT SINGLE CELL RESOLUTION The brain is the most complex organ in our body, consisting of many different cell types. We map the cellular changes that occur during disease and aging, but also specific behaviors such as sleeping and learning. We develop the next generation of technology to measure cellular function at much higher resolution and to maintain spatial information on the location of each individual brain cell. Researchers in our Center produced the first complete map of all the cells of the entire fruit fly, and mapped the changes that occur during aging, while others have defined the types of glial support cells (astrocytes) at unprecedented resolution. 5
STEIN AERTS LABORATORY OF COMPUTATIONAL BIOLOGY We are interested in decoding the genomic regulatory code and understanding how genomic regulatory programs drive dynamic changes in cellular states, both in normal and disease processes. SANDRINE DA CRUZ LABORATORY OF NEURODEGENERATIVE DISORDERS AND NEUROPHYSIOLOGY Our lab studies the role of local axonal translation in neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), as well as the spreading of RNA binding proteins, including FUS and TDP‑43, in ALS. The team also focuses on muscle innervation and the development of new therapeutic targets to treat neuromuscular disorders including ALS. WIM ANNAERT LABORATORY FOR MEMBRANE TRAFFICKING Our laboratory is focused on understanding the molecular biology of membrane transport in a disease-related context covering Alzheimer’s and Lewy Body diseases. BART DE STROOPER LABORATORY FOR THE RESEARCH OF NEURODEGENERATIVE DISEASES We investigate the basic mechanisms causing Alzheimer’s disease starting from the genetic forms of the disorder. We study the complex cellular phase of Alzheimer’s disease using single cell, genome wide transcription profiling with spatial and temporal resolution. LUCÍA CHÁVEZ-GUTIÉRREZ LABORATORY OF PROTEOLYTIC MECHANISMS MEDIATING NEURODEGENERATION JORIS DE WIT We want to generate a quantitative understanding of the Our brain is made up of billions of neurons that are precisely molecular mechanisms underlying Alzheimer’s disease pathogenicity, more specifically the biochemical function of the molecules involved in familial Alzheimer’s disease. LABORATORY OF SYNAPSE BIOLOGY connected into neural circuits, forming an immensely complex network that encodes our thoughts, memories and personalities. Our lab aims to unravel the molecular mechanisms that control neuronal connectivity in developing circuits, and determine how perturbations in this process affect cognitive function. Meet our group leaders 7
LABORATORY OF NEUROBIOLOGY LYNETTE LIM LABORATORY OF INTERNEURON DEVELOPMENTAL DYNAMICS Our research focuses on the mechanisms of acute and chronic axonal and neuronal degeneration and regeneration. We aim to contribute to the development of new therapeutic strategies for neurodegenerative disorders, such as motor Information processing in the brain depends on specialized circuits that are formed by distinct types of neurons. We neuron diseases (ALS and hereditary motor neuropathies), frontotemporal dementia (FTD) and stroke. study the metabolic and transcriptomic programmes that shape neuronal diversity and circuit assembly in the developing mammalian cortex. PIERRE VANDERHAEGHEN STEM CELL AND DEVELOPMENTAL NEUROBIOLOGY LABORATORY The major research goal in our laboratory is to understand the molecular and cellular mechanisms underlying the development and evolution of the cerebral cortex, from SHA LIU LABORATORY OF SLEEP AND SYNAPTIC PLASTICITY stem cells to neuronal circuits, from mouse to man, in health and disease. Sleep is a fundamental and evolutionarily conserved behavior, and the only major behavior for which the function remains unknown. The goal of our lab is to understand the synaptic and circuit mechanisms underlying sleep and its function in the brain. PATRIK VERSTREKEN LABORATORY OF NEURONAL COMMUNICATION The earliest stages of neurodegenerative diseases such as dementia and Parkinson's disease are characterized by synaptic problems. We probe into the diverse molecular mechanisms at the basis of neuronal degeneration and synaptic dysfunction, and how we can reverse this process. FREDERIC ROUSSEAU & JOOST SCHYMKOWITZ SWITCH LAB Our work uses patient-derived iPS cells and human microcircuits, rodents and powerful fruit fly genetics. We study the mechanisms gearing protein folding and misfolding and their relation to human disease. In particular, we investigate how protein aggregation affects the interactome by suppressing native interactions but also by introducing novel aggregation-specific interactions. THOMAS VOETS LABORATORY OF ION CHANNEL RESEARCH We focus on a superfamily of cation channels, the transient receptor potential (TRP) channels, which includes 27 human members. There is a striking diversity in the stimuli that can regulate the gating of the TRP channels, which include physical stimuli such as temperature and voltage, as well as various endogenous and exogenous chemical ligands. Meet our group leaders 9
MATTHEW HOLT VISITING PI 2022 // I3S, UNIVERSITY OF PORTO Astrocytes are the most abundant glial cell in the mammalian central nervous system. The goal of our group is to understand the molecular mechanisms that control astrocyte development and function in vivo. We are particularly interested in the role of astrocyte-neuron interactions and how they shape activity in both the healthy and diseased brain. FRANCK POLLEUX VISITING PI // COLUMBIA UNIVERSITY Our research provides new insights into the cellular and molecular mechanisms underlying the establishment and maintenance of brain connectivity and has significant implications for our understanding of the pathophysiological mechanisms underlying socially-devastating neurodevelopmental disorders and neurodegenerative diseases. WE ARE PART OF AN EXCEPTIONALLY RICH NEUROSCIENCE COMMUNITY Leuven and Flanders are home departments and faculties, at the to a diverse neuroscience scene, university hospitals in Leuven and including our VIB-KU Leuven Cen- at the nearby institute for micro- ter for Brain & Disease Research, electronics, imec. The exception- NeuroElectronics Research Flan- ally rich neuroscience community ders (NERF) and the VIB-UAntwerp in Leuven comes together under Center for Molecular Neurology. the umbrella of the Leuven Brain Furthermore, there is an exciting Institute, and we are part of nu- and broad group of neuroscience merous international collaborative faculty at the KU Leuven across networks, including CURE-ND. The VIB Neuroscience group leader community at a joint retreat in June 2022 to discuss new collaborative projects 11
We study what causes neurodegenerative disease SOME FORMS OF ALZHEIMER’S DISEASE HIT EARLY IN LIFE, CAN WE PREDICT WHEN? We study pain mechanisms INFLAMMATION SETS OFF SENSORY ALARMS The research team of Thomas Voets uncovers how the upregulation of an ion channel called TRPM3 causes hypersensitivity in inflamed tissue. The new findings, published in eLife, suggest new therapeutic avenues to help patients suffering from chronic pain. Whenever you touch a hot pan, you withdraw your hand within a fraction of a second. Likely, you will also immediately feel a burning pain. This acute pain is actually a good thing—it functions as an alarm signal, warning you that high temperatures can cause dangerous and potentially life-threatening injuries. Sometimes this alarm system can become deregulated, for example upon tissue inflammation or injury. Nerve impulses can then be initiated at temperatures that are normally non-painful, and as a result, you may experience burning pain when taking a shower or walking in the sun, or, in the worst case, all the time. Thomas Voets and his team try to understand the mechanisms that underlie this type of hypersensitivity and how it may lead to chronic pain, in the hopes to ultimately find novel pain treatments for patients. Temperature sensors and inflammation Voets and his team have a particular interest in socalled TRP ion channels—proteins that allow the flow of charged ions across membranes to induce electrical signals. He explains why: “From earlier research, we knew that three such TRP ion channels act as the temperature sensors that initiate an acute pain response to heat. To better understand the mechanisms behind hypersensitivity, we wanted to know whether these three TRP channels, known as TRPM3, TRPA1 and TRPV1, become deregulated in inflamed tissue.” The researchers used a mouse model to study local inflammation of the hind paw. “For one of the ion channels, TRPM3, we found differences in gene expression between the inflamed and the unaffected paw,” explains Marie Mulier, a PhD student in Thomas Voets’ lab and first author on the study. “TRPM3 expression was higher in the sensory neurons that innervate the inflamed hind paw compared to the other, unaffected paw.” Reducing hypersensitivity By measuring the activity of the sensory neurons, both in the fine endings in the skin and in their cell bodies close to the spinal cord, the researchers found that all three heat-activated TRP channels become hyperactivated in neurons that innervate the inflamed paw, explaining the increased heat sensitivity. But interestingly, a compound that inhibits the function of TRPM3 restored the sensitivity of the sensory neurons to normal levels. “Our findings suggest that increased levels of TRPM3 in sensory neurons represent an important driver of inflammatory hypersensitivity to heat,” says Voets. “Therefore, drugs that dampen TRPM3 activity may become a viable therapy to reduce pain and hypersensitivity in patients.” Upregulation of TRPM3 in nociceptors innervating inflamed tissue Mulier et al. 2020 eLife Explore our science Familial Alzheimer's usually hits relatively early in life, affecting people in their forties or fifties, or sometimes even earlier. The research team of Lucía ChávezGutiérrez has uncovered a direct relationship between changes in the amyloidbeta fragments that accumulate in the brain tissue of Alzheimer’s patients, and the age at which symptoms first arise. The researchers hope we can use these insights not only to predict but eventually also to delay disease onset. When do Alzheimer’s symptoms first appear? In most cases, Alzheimer’s disease is not inherited and starts to manifest after the age of 65. In rare cases, however, Alzheimer’s can be passed on in families and this familial form typically also manifests much earlier in life, affecting people in their forties or fifties, or sometimes even already in their twenties or thirties. Although familial Alzheimer's is rare, close to 400 different mutations have been identified in families with early-onset Alzheimer’s around the globe. They can all be traced back to the same small set of genes encoding the molecular machinery that generates amyloid beta fragments in the brain. “In collaboration with our clinical partners, we were also able to use this linear correlation for the experimental assessment of age at disease onset of mutations for which there had been limited family history or a complex clinical picture,” adds Sara Gutiérrez Fernández, another PhD student closely involved in the study. “Interestingly, the age at which clinical symptoms first manifest is relatively consistent within families and between carriers of the same mutations, but differs markedly between mutations,” says Lucía ChávezGutiérrez. “It is important to understand the mechanisms by which some mutations cause symptoms to manifest decades earlier than others,” she says. “Not only because of the practical importance for families affected by familial Alzheimer’s, but also to understand how we could conceive to halt or at least delay disease.” Chávez-Gutiérrez: “Our ultimate question is: can we shift the molecular composition of brain amyloid profiles in such a way that we can delay symptom onset? This is a fundamental question, that we cannot answer in a definitive way today, but our results do support exploring the therapeutic potential of compounds that could tweak amyloid-beta production with the aim of generating shorter fragments.” She stresses that even today, being able to predict the age of disease onset based on amyloid-beta profiles, could be really helpful in clinical settings: “Information on how a certain mutation affects amyloid processing, together with the clinical picture of a patient, can help us determine whether the mutation is indeed causative. We have already been able to clarify this for multiple mutations, which means families can receive adequate genetic counseling and gain access to clinical trials.” A linear correlation Chávez-Gutiérrez’ team analyzed the amyloid-beta fragments generated by 25 different mutations discovered in families presenting with Alzheimer’s symptoms at ages varying from 25 to 60 years. “We found that changes in the molecular composition of amyloid-beta correlated linearly with the age at disease onset,” says dr. Dieter Petit, a recently graduated PhD student in the lab. “Clearly, longer amyloid-beta fragments are more abundantly present in mutant amyloid-beta profiles linked to earlier symptom onsets.” From biochemistry to therapy? While the study involves mutations linked to rare familial forms of Alzheimer’s, all Alzheimer’s cases are characterized by amyloid-beta deposition in the brain, and clearly common pathways eventually result in the development of the same collection of symptoms. Abeta profiles generated by Alzheimer's disease-causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset Petit, Gutiérrez Fernández et al. 2022 Mol Psychiatry 13
PROTEINS OF A FEATHER FLOCK TOGETHER Researchers from the Switch lab, led by Joost Schymkowitz and Frederic Rousseau, predict how highly similar proteins speed up or halt protein aggregation in Alzheimer’s and other brain diseases. Different neurodegenerative diseases such as Alzheimer’s and Parkinson’s have one thing in common: one particular protein clumps together, first in one part of the brain, later spreading across other regions, causing increasingly severe symptoms. A research team led by Joost Schymkowitz and Frederic Rousseau has now uncovered how highly similar protein segments can speed up—or more interestingly—thwart this aggregation process, potentially explaining the specific vulnerability of certain brain regions and hinting at potential new ways to develop improved therapeutics. Protein aggregates as the common thread What neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, ALS and a whole range of others have in common, is the fact that the brains of deceased patients are riddled with protein inclusions. The identity of the proteins differs, but the sequence of events is similar. Certain proteins become structurally abnormal. Often the culprit proteins fail to fold into their normal configuration; and in this misfolded state, the proteins wreak havoc or lose their normal function, either way disrupting the normal function of brain cells or tissues. The end result: degeneration of certain brain tissues, leading to the diverse disease symptoms featured by neurodegenerative disorders. Why some protein aggregation starts in a specific brain region—like the region important for memory in Alzheimer’s or the region involved in steering movements in Parkinson’s disease—remains unclear. Finding the trigger(s) Frederic Rousseau and Joost Schymkowitz have built their careers studying the biochemistry of how proteins fold and why they misfold. In two new studies, they report how thousands of proteins in our cells bear sequences that resemble the aggregation-prone regions of the culprit proteins involved in Alzheimer’s disease. These ‘third-party proteins’ may play a meaningful part in disease progression, and—more importantly—a potential treatment. Explore our science “Aggregation-prone regions are short segments with a high propensity to clump together into the sticky structures that essentially make up these disease-related aggregates,” explains Rousseau. “The short segments may be part of bigger proteins, and while they typically stick to each other, we wondered whether other proteins with the same or similar regions could also set off this aggregation cascade.” "Thousands of proteins bear sequences that strongly resemble aggregation-prone regions of amyloids, allowing them to boost or halt the aggregation process." Katerina Konstantoulea A grammar for protein aggregation? The team set out to look for other proteins containing similar aggregation-prone regions as those found in amyloid beta, the culprit peptide found in Alzheimer’s plaques. Finding many of those, they tested 600 proteins for potential interaction with amyloid beta, explains Katerina Konstantoulea, PhD student in Schymkowitz and Rousseau’s lab: “Thousands of proteins bear sequences that strongly resemble aggregation-prone regions of amyloids, allowing them to interact and either boost or halt the aggregation process.” The researchers designed a peptide and experimentally tested its capacity to inhibit tau aggregate formation To understand why some similar proteins pushed aggregation while others slowed it down, postdoc Nikolaos Louros looked at nearly a hundred aggregationprone regions, including those for disease-related amyloid beta, tau, and α-synuclein—which aggregate in Alzheimer’s and Parkinson’s disease, respectively. Using computational methods, Louros modeled all the ways in which changes to the sequence of the aggregation-prone regions would affect their propensity to stick together. “We found that most changes reduced aggregation capacity in some way,” says Louros. “Some by changing the rate of aggregation, others by hindering their spread, still others by modifying the nucleation process or the morphology of the aggregates.” Designing aggregation-blocking peptides Using this newly gained information and with tau as an example, Louros and his colleagues tried to design a peptide that would block tau aggregation. In vitro and in cell lines, their synthetic peptide turned out to block tau aggregation and spread five-fold more effectively compared to previous designs, suggesting that this approach could indeed be promising for the development of new therapeutics. “Our findings indicate that the proteomic background of cells and tissues can modulate the aggregation propensity of culprit proteins, which could explain—at least in part—the selective vulnerability we observe for many of these proteins and diseases,” says Schymkowitz. “Importantly, we can also try to exploit this information to improve therapeutics against several of these neurodegenerative diseases.” Heterotypic amyloid β interactions facilitate amyloid assembly and modify amyloid structure Konstantoulea et al. 2022 EMBO J Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers Louros et al. 2022 Nature Comms 15
TARGETING TAU TO KEEP NEURONS CONNECTED An international team of researchers led by Patrik Verstreken has succeeded in reversing the effects of Tau, a protein implicated in over 20 different diseases, including Alzheimer’s disease. The promising findings in animal models are an important first step in the exploration of a new therapeutic avenue targeting cognitive decline. The Tau protein is implicated in numerous neurodegenerative disorders, sometimes called ‘tauopathies’, including Alzheimer’s disease and other types of dementia. In all these diseases, Tau causes havoc by aggregating within neurons. While such Tau aggregates are closely correlated with cognitive decline, we still don’t fully understand how they cause it. “In tauopathies, we observe inflammation and loss of neuronal connections in the brain, even before Tau aggregates start to form on a massive scale,” says Patrik Verstreken. Verstreken and his team are specialized in neuronal communication and its links to disease. They teamed up with colleagues at the UK Dementia Research Institute to explore how the different aspects of the disease process lead to the cognitive symptoms induced by Tau. Partner in crime The team turned their attention to another neuronal protein: Synaptogyrin-3. It is one of the proteins Tau interacts with, but it can only be found in the vicinity of neuronal connections, explains Pablo Largo Barrientos, PhD student in the Verstreken lab: “Since Synaptogyrin-3 is only present near neuronal connections, we interfered with its function to determine the role Tau plays specifically at this location.” By eliminating Tau’s partner in crime in a mouse model, the researchers could prevent the loss of neuronal connections that Tau would normally induce. “We also found that the working memory of these mice didn’t decline as we’d normally expect,” adds Pablo. Intriguingly, however, the inflammation effects remained the same. This led the researchers to propose that Tau induces inflammatory effects and loss of connectivity independently, and that the latter is a major determinant of cognitive decline. "We found that the working memory of these mice didn’t decline as we’d normally expect. " Pablo Largo Barrientos A window of opportunity “Our work provides the first evidence that it is possible to rescue the loss of neuronal connections and memory impairment, namely by targeting Tau specifically where neurons connect,” says Patrik. The researchers are now developing drugs that could decrease Synaptogyrin-3 levels in the brain. With those, they plan to test the therapeutic value of this approach for tauopathies, eventually in patients. Lowering Synaptogyrin-3 expression rescues Tau-induced memory defects and synaptic loss in the presence of microglial activation Largo Barrientos et al. 2021 Neuron We develop new models TRANSPLANTING HUMAN MICROGLIA A team of scientists led by Bart De Strooper (VIB-KU Leuven) and Renzo Mancuso (VIB-UAntwerp) published a protocol to study human microglia in the context of the mouse brain. Microglia are the immune cells of the brain, and they play a crucial role in neurodegenerative disease processes. With their protocol called MIGRATE, they provide a step-by-step workflow that includes in vitro microglia differentiation from human pluripotent stem cells, followed by transplantation into the mouse brain and subsequent quantitative analysis of the engraftment. The entire protocol takes approx. 40 days. Microscopic image of a section of the hippocampus: the yellow zone contains the synaptic connections where Tau and Synaptogyrin-3 are enriched (Pablo Largo Barrientos, Verstreken lab) Explore our science Stem-cell-derived human microglia transplanted into mouse brain to study human disease Fattorelli, Martinez-Muriana et al. 2021 Nat Protocols 17
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