The ESRs will pursue 15 different PhD projects, distributed at six organisations.
Karolinska Institutet, Stockholm, Sweden
Read more about Eduardo and his project
I graduated from Amherst College in Massachusetts, USA with a bachelor’s degree in Neuroscience. I then went on to obtain a Master of Science degree in Medical Neurosciences at Charité Universitätsmedizin Berlin in Germany. My interest in neuroscience burgeoned after being selected as a Howard Hughes Medical Institute research fellow to conduct a study on forebrain function of the melanocortin receptor. Later on in my career, I developed a more specific focus on molecular neurobiology and neurodegenerative disorders, and pursued projects on chronic pain, Alzheimer’s disease and Huntington’s disease. My master’s thesis project assessed the contribution of mutant huntingtin expression in microglia to the pathological hallmarks of this latter disorder.
Genetic, in vitro, in vivo and epidemiological findings have highlighted the importance of cholesterol metabolism in Alzheimer’s disease. Preliminary results from our group show that oxysterols—a class of cholesterol metabolites- have a role in synaptic maturation defects in AD. Thus, our project’s initial goal will be to characterize how oxysterols affect adult neurogenesis and spine formation in newborn neurons. To achieve this, we will use in vitro as well as recently developed in vivo models of altered cholesterol metabolism. Subsequently, the next stage of the project intends to use the insight gained into the basal mechanisms by which oxysterols modulate synaptic maturation to selectively target cholesterol metabolism as a possible modifying therapy for early synaptic loss and early biomarker discovery tool in Alzheimer’s.
Read more about Hazal and her project
I am originally from Turkey and graduated from Istanbul University with degrees in Molecular Biology and Genetics (BSc) and Neuroscience (MSc). I then worked as a research scientist in Dr Laura Parkkinen’s lab in Nuffield Department of Clinical Neurosciences, University of Oxford, where I investigated how the risk genes of Parkinson’s disease may influence the heterogeneous end-point pathology. SyDAD provides an excellent environment for us, which is fueled with innovative research facilities and training programs. My PhD project aims to identify proteins that are indeed involved in synaptic dysfunction in AD, which could potentially serve as targets of pharmaceutical intervention and/or biomarkers for synaptic degeneration.
This PhD project aims to elucidate the pathways underlying altered synaptic degeneration and amyloid-beta (Aβ) metabolism in Alzheimer’s disease (AD). Although the widely accepted amyloid cascade hypothesis postulates that Aβ acts as the primary driving force of AD pathogenesis, studies have shown that synaptic degeneration may be one of the earliest pathological events in AD. Therefore, mechanisms underlying synaptic degeneration may also occur upstream of Aβ, affecting its production and/or secretion, and possibly triggering its downstream cascade even further. This can be supported by the fact that synaptic activity can increase the levels of secreted Aβ. The mechanisms behind synaptic degeneration remain to be established, as well as their possible link to Aβ metabolism. Therefore, we aim first to identify differentially expressed proteins in AD (by using human post-mortem brains), and then to decipher whether these proteins can trigger synaptic dysfunction and/or dysregulated Aβ metabolism (by using animal model and in vitro studies).
Bordeaux 2017 for 4 months: To study the effect of the identified proteins on synaptic function.
Gothenburg 2019: To evaluate the identified proteins as biomarkers
ESR 13: Neurophysiological markers of synaptic dysfunction in Alzheimer’s disease
PhD student:Una Smailovic(email@example.com)
Main supervisor: Vesna Jelic (firstname.lastname@example.org)
Co-supervisors: Per Nilsson (email@example.com),Kina Höglund (Kina.Hoglund@neuro.gu.se), Susanne Frykman (firstname.lastname@example.org)
Read more about Una and her project
I am a medical doctor graduated from School of Medicine, University of Zagreb, Croatia with previous research experience in the field of Alzheimer’s disease and its potential therapeutics gained at my home university and through several exchange programs. I applied for a PhD position within SyDAD European Training Network since it was an an unique opportunity for a research project with translational orientation that incorporates both clinical and experimental studies of AD. Moreover, high quality doctoral education at Karolinska Institutet, meetings and courses held by word-leading scientists from notable academic institutes and an ongoing collaboration with other PhD students within SyDAD will provide me a crucial insight into advanced pathophysiological mechanisms behind AD. My research project is focused on evaluating novel qEEG and CSF biomarkers and their potential in algorithmic approach used in early symptomatic preclinical diagnosis of AD which might yield a critical opportunity for an intervention with disease modifying therapy.
Electroencephalography (EEG) reflects summated electrical activity at the level of functional units of the brain – synapses. Consequently, EEG should be a method of choice to study continuum of cognitive decline in Alzheimer’s disease (AD), from preclinical and predementia stages with only subjective cognitive decline or objectively verified mild cognitive impairment (MCI) towards clinically manifest disease. Typical EEG, in particular quantitative EEG (qEEG) phenotypes of MCI and early AD have been described and correlated to disease severity and other surrogate markers of cerebral function.
The aim of this project is to investigate association of qEEG parameters with FDG-PET glucose metabolism which reflects topography and dynamics of neuronal dysfunction, conventional CSF biomarkers of core AD molecular pathology and novel CSF biomarkers of synaptic dysfunction in well defined patients with a wide spectra of preclinical and clinical disease severity. Furthermore, we aim to introduce a translational model of evaluating novel CSF synaptic markers by investigating their relation to cognitive dysfunction, regional metabolic alterations and neuropathology in a transgenic mice model of AD.
Electrophysiological markers of synaptic dysfunction that characterize a valid and reliable phenotype as well as disease activity may serve as valuable early diagnostic markers of AD and outcome measures in treatment trials with disease modifying drugs.
Planned secondments: University of Gothenburg
Read more about Giacomo and his project
After graduating from high school in Sardinia (Italy), I decided to move to the UK where I got accepted at King´s College of London for a BSc in Biomedical Science and MSc Neuroscience in Neurodegeneration. SyDAD is a unique PhD programme for its international collaborative approach and its emphasis on high level bioscience training. Our project will elucidate the role of mitochondria and particularly MAM dynamics in synaptic-related dysfunction in AD, a so far never investigated aspect of the disorder. Moreover, we seek to find effective mitochondrial stabilisers that will lead to improved synaptic phenotype. From both studies we hope to gain further insight into potential therapeutic strategies to improve or stop deterioration of cognitive function seen in this fatal condition.
Synaptic failure and degeneration have been shown to correlate with cognitive decline in Alzheimer’s disease (AD).
It is also well reported that mitochondrial function is widely impaired in AD. Mitochondria have several important roles in the cell including energy production, lipid synthesis, regulation of calcium homeostasis and apoptotic signalling.
In order to function properly mitochondria need to interact with the endoplasmic reticulum (ER) at specialized contact sites, known as mitochondria-associated ER membranes (MAM). Interestingly, MAM function is altered in models of AD.
We hypothesize that i) mitochondrial and MAM dysfunction cause synaptic failure leading to impairment of cognitive function ii) mitochondrial stabilizers protects against synaptic failure and are beneficial for treatment of AD.
We aim to identify compounds that stabilize mitochondrial function in a high-throughput screen (HTPS) and to test lead candidates in cellular and animal models of AD. Read outs include measurements of spine density, dendritic branching, expression of synaptic proteins, synaptic and mitochondrial function. In parallel studies, modulation of ER-mitochondria contact and its impact on synapses will be investigated.
Planned secondments: Alzecure (Stockholm), DZNE, Bordeaux University
Associated students at Karolinska Institutet
Jolanta Lundgren: Synaptic production and release of Aβ
I am originally from Finland where I did my Master in Cell Biology at Åbo Akademi University in Turku. I had a fantastic exchange year in Scotland at the University of Aberdeen where I focused my studies on Neuroscience and where my astonishment for the complexity of the brain was further increased. I am very happy to be connected to SyDAD as an associated student and feel this is a wonderful opportunity for me to obtain more skills in synaptic research and get a wider scientific network which I know I will benefit from throughout my future career. When we have managed to identify the mechanism of Aβ release, further studies to modify this release could lead to new therapeutic approaches which are highly desired by the AD patients, their families and the whole community.
I study the role of the amyloid-beta peptide (Aβ) at synapses in AD. I´m particularly interested in where Aβ is produced and how it is secreted from synapses. My group and I have shown that Aβ is constantly released from synapses at physiological temperature (37 °C) by a mechanism distinct from that of neurotransmitters (Lundgren et al. 2014). Currently I´m using lentiviral transduction of mouse primary cortical neurons to silence genes involved in internal trafficking within cells. This way I hope to interfere with synaptic Aβ release and consequently discover the mechanism of this release.
Aβ is produced by the sequential cleavage of the amyloid precursor protein (APP) by first β-secretase (mainly BACE1) and then γ-secretase. Cleavage of APP by the α-secretase ADAM10 instead of BACE1 precludes Aβ production. We have shown that although Aβ can be produced in synaptic vesicles, the main production occurs elsewhere since the components of the γ-secretase complex are not enriched in synaptic vesicles compared to total brain homogenate (Lundgren et al. 2015). Yet, the first step in the cleavage process most likely takes place in synaptic vesicles since both ADAM10 and BACE1 are highly enriched in these vesicles. Following up these results I am now investigating the synaptic localization of the secretases in human AD and control brain using proximity ligation assay (PLA).
Nuno Leal: Modulation of ER-mitochondria interplay in Alzheimer’s disease: effects on amyloid β-peptide generation, autophagy and mitochondrial function.
I am originally from Porto, Portugal where I obtained a Bachelor of Science from University of Porto. After finishing my degree I moved to Sweden were I obtained a Master of Science at Stockholm University.
I am currently on my second year of my PhD studied. I am part of Maria Ankarcrona’s group at Karolinska Institutet, Sweden. Currently, we are working with Mitochondria-ER associated membranes (MAM) and Alzheimer’s disease (AD). In our group we try to understand the role between this subcellular structure and AD with special interest in Amyloide β-peptide production and autophagosome formation/maturation at MAM.
As one of the associated students from SyDAD I expect to expand my network and knowledge about neurodegenerative disorders and synapses as well as promote our line of research. Our research will help enlightening the mechanisms behind AD and to identify possible new drug targets.
Julen Goicolea: Cholesterol Metabolism, oxysterols and Alzheimer´s disease
I am originally from Bilbao, Spain and graduated from the university of the
Basque Country (UPV/EHU) with a degree in Biotechnology. Then I moved to the Netherlands where I obtained a Master’s degree in biomedical sciences at
Groningen University. During that time I did my master project in the Neuroscience department, University Medical Centre Groningen (UMCG), under the supervision of Dr Bart Eggen. There I investigated the molecular mechanisms behind the endotoxin tolerance of microglia upon subsequent Toll-like receptor activation. My PhD project aims to investigate the biological roles of oxidized cholesterol metabolites, oxysterols, in the brain and how alterations in cholesterol metabolism participate in neurodegenerative processes such as AD.
Project 1: Unraveling the role of oxysterols in cognition.
We hypothesized that overexpression of the enzyme responsible for the
generation of 27-hydroxycholesterol (Cyp27) will increase synaptic and
behavioral deficits in mice and the opposite in the case of overexpression of the enzyme responsible for the generation of 24S-hydroxycholesterol (Cyp46).
We will characterize our Cyp mice models using a combination of behavioral and
biochemical tests. Recent studies in our lab showed in Cyp46 females show
improvement in memory compared to controls. Moreover, we will measure
different molecules related to AD (including Ab and P-tau) and cognitive
impairment such as ARC and NMDA-dependent signalling, synaptic proteins and
brain glucose metabolism.
Project 2: Oxysterols and cognitive performances in human subjects
Our hypothesis is that there is a “risk” population of high cholesterol metabolizers
with cognitive impairment due to excessive 27-hydroxycholesterol (27OH).
We will evaluate if this “risk population” can be identified in large clinical cohorts
and if multimodal intervention in elderly can influence such disease mechanism.
Also, identified biomarkers in our animal studies will be test in human blood from
these cohorts, to further explore whether they are a suitable blood biomarkers for
detecting subtle cognitive alterations that lead to a neurodegenerative disorder.
Main supervisor: Angel Cedazo-Minguez (Angel.Cedazo-Minguez@ki.se)
University of Bordeaux, France
Read more about Tomas and his project
Originally I come from Palma de Mallorca in Spain. I studied Health Biology in the University of Alcala de Henares in Madrid. Afterwards I decided to go abroad as an Erasmus student to do my bachelor’s final project in Amsterdam at the Vrije University. At this university I complemented my studies doing a master in Neurosciences.
The SyDAD program gave me the chance to find a project where the combination of fundamental research and clinical research in AD was compatible. Furthermore, it is also a great opportunity to meet and collaborate with other international students and top research scientists from different fields related with AD. Therefore SyDAD program will allow me to improve my skills as a researcher, using them as a value to improve scientific knowledge and society progress.
Personally I think that neurodegenerative diseases such as AD will only be cured if we fully understand the molecular mechanisms where affected proteins are involved. Therefore I hope that my research will contribute to understand the molecular processes where APP is involved at the presynaptic level. In addition, I hope that our project will open new research lines to develop drugs that could prevent, stop or reverse AD.
The Amyloid Precursor Protein (APP) is enriched in presynaptic terminals and interacts with protein partners essential to the release of synaptic vesicles (SVs) suggesting a key role in presynaptic mechanisms.
The aim of our project is to study the role of APP in presynaptic mechanisms by combining super-resolution microscopy with project-designed optogenetic tools coupled to electrophysiology in order to decipher the roles of the different APP fragments.
We will examine the expression pattern (confinement, mobility) at the presynaptic terminal of APP-tagged with a photoactivable fluorescent protein in neurons by super resolution microscopy (SPT-PALM). We will investigate different fragments of APP (the full-length form, the beta-secretase generated fragment: beta-CTF, the intracellular fragment generated by gamma-secretase: AICD).
Then, we will study in brain slices the role of selected APP mutants in synaptic function by using new optogenetic tools which combine cell-specific activation by channelrhodopsin (ChR) to genetic manipulation.
Finally, in conditions where an APP mutant impairs presynaptic mechanisms we will evaluate the ability of some gamma-secretase modulators (GSMs) candidates to restore physiological neurotransmission.
Overall, our project will reveal new insights about the physiological role of APP in neurotransmitter release and how this function is impaired by pathological conditions.
Planned secondment: Karolinska Institutet
Read more about Ania and her project
I am from Lisbon, Portugal, and I hold my MSc in Biotechnology from Universidade Nova de Lisboa. I did my master project at Instituto de Salud Carlos III, Madrid, which was focused on regulation of adult neural stem cells in hippocampus of Alzheimer’s disease (AD) mouse models. Then, back to Portugal I’ve started working as microscopy technician at Gulbenkian Science Institute, Oeiras.
The prestigious organizations that are involved and the opportunity to conduct my own research were some of the key reasons that motivated me to apply for this program.
SyDAD program provides me a good chance to learn from specialists in the field, and the possibility to work in both academic and pharmaceutical environment. This helps me to constantly develop my skills, greatly thanks to SyDAD’s excellent network. My goal is to contribute with new evidences to understand the synaptic dysfunction in AD as a complement of all Sydad’s projects. All results together can lead to advancements in the clinical field and ultimately improve the AD patient’s quality of life.
Hyperphosphorylation of the tau protein and its accumulation as intraneuronal tangles are hallmarks of Alzheimer disease (AD). Increasing evidence suggests that they impair axonal transport of mitochondria and mitochondrial respiration, which could partially explain mitochondrial dysfunctions observed in AD.
Mitochondria are critical for synaptic function, in part through ATP supply and calcium buffering. This project aims at determining whether mitochondrial impairment by defective tau causes synaptic dysfunction in AD.
We will focus on the hippocampus, a key memory structure, and study the progressive deterioration of mitochondrial and synaptic functions in relation to the spreading of tau aggregates in a tau seeding model.
Tau seeding will be implemented in hippocampal organotypic slices to allow the monitoring of mitochondrial trafficking and function, using confocal imaging, and of synaptic transmission and plasticity, using electrophysiology.
Planned secondments: Janssen Pharmaceutica NV.
Read more about Dario and his project
I am a PhD Student from Turin, Italy. I obtained my MSc degree in Molecular Biotechnology at the University of Turin. Working in a Neuroscience lab has been constantly tickling my interests, making me develop a deep enthusiasm in exploring this subject. I applied to SyDAD program because it offers me the possibility to give a significant contribution to this field in the future, providing the chance to perform outstanding research. The ambitious mission of SyDAD program is to create a great world-wide group of young researchers, bound together by the same ultimate goal. Each SyDAD researcher will therefore take advantage of flows of ideas, mutual suggestions, and shared competences and resources. Thanks to these principles, I am confident the whole community will benefit from SyDAD research.
One of the earliest cognitive deficits observed in Alzheimer’s disease (AD) is a progressive impairment in memory encoding abilities, initially limited to episodic memory. In project ESR 12 I am interested in exploring the mechanisms governing the establishment of episodic memory, and in investigating how these processes are impaired in the early stages of AD.
The hippocampal CA3 region is involved in episodic memory storage and retrieval. Neurocomputation has proposed a prominent role for synaptic plasticity of the CA3 autoassociative network for rapid encoding of information.
The ultimate goal of the project is to establish a link between the activity of CA3 circuits and episodic memory encoding in the intact brain and to explore how this is affected by synaptic dysfunction in AD mouse models (APP/PS1 mice and a Tau-related mice model in my secondment at Janssen Pharmaceutical, Antwerp, Belgium).
To this end, the project will combine new viral tracing approaches and behavioural assessment in order to label “memory-activated” neurons in CA3. Slice and in vivo electrophysiology combined with optogenetics will be used to compare the properties of “memory-activated” CA3 neurons in control conditions and in models of AD.
This model circuit for the storage mechanisms of episodic memory can be used to test pharmaceutical compounds. In fact, my team has recently described a marked impairment in the plasicity of CA3 circuits in a mouse model of AD which depends on the overexpression of the adenosine A2A receptor (Viana da Silva et al, Nat Comm 2016). In particular A2A receptor antagonists will be possibly tested in this context as a putative interventional target, in order to try to reverse the memory deficits.
Planned secondments: Janssen Pharmaceuticals
Associated students at University of Bordaux:
Nan Jiang: Inflammatory PGE2-EP3 signaling in a mouse model of Alzheimer’s disease
I am from China and finish my Master degree in Shanghai University. From the SYDAD program, communicated with students from different labs benefited me a lot for the basic knowledge in AD. And my project raises the promising idea that the EP3 signaling pathway may prove to be a specific target for therapeutic strategies, more advantageous and less deleterious than the global inhibition by NSAIDs.
In cognition and memory processes, DG-CA3 circuits play a key role in the encoding of new spatial information and complex mnemonic processes and alterations of Mf-CA3 synaptic function and plasticity are likely to contribute to AD-related cognitive deficits.
Aim of the project
1. To determine a cognitive deficit in APP/PS1 mice
Now we need to test Object Pattern Separation, because it can investigate spatial pattern separation, which utilizes memory processes centered in the DG and CA3 region of the hippocampus. Once done, we will test if blocking PGE2-EP3 signaling pathway to block the expression of EP3 receptors in DG will rescue behavioral impairment.
2. To study if APP/PS1 females display Mf-CA3 presynaptic deficit.
We will investigate by either patch clamp recording or by field recording if LTP in APP/PS1 female mice at 6 months is altered. In the case of an impairment of LTP, we will test the effect of the EP3 antagonist (ONO-AE3-240).
3. To investigate if PGE2-EP3 signaling underlie cognitive deficit2
We will test the effect of the genetic impairment of EP3 receptors by miRNA EP3 on the behavioral test determined in Task 1. PGE2-EP3 signaling pathway is linked to behavioral deficits and if blocking this pathway may alleviate these deficits. And impairments and/or deficits of presynaptic plasticity and behavioral in females.
We will test the effect of administration of ONO-AE3-240 by intraperitoneal route on the behavioral test determined in Task 1. This remains to be investigated in females APP/PS1 at 6 months of age.
University of Milano, Italy
ESR 1: Linking actin-dependent dendritic spine remodelling and ADAM10 activity in AD: the role of CAP2.
PhD student: Lina Vandermeulen (email@example.com)
Main supervisor: Monica di Luca (firstname.lastname@example.org)
Co-supervisors: Elena Marcello (email@example.com), Fabrizio Gardoni (firstname.lastname@example.org)
Read more about Lina and her project
My name is Lina Vandermeulen and I was born in Amsterdam, the Netherlands. This is also the city where I obtained my Bachelor’s and Research Master’s Degree in Neurosciences. After I finished, I was determined to apply for a PhD position, and because my main interest are Neurodegenerative diseases together with molecular biology/biochemistry, the project in Monica DiLuca’s lab suited perfectly. I hope to succeed in concluding the aims of the project, so the research I complete can be a contribution in figuring out the complex background of AD. Since there are many inspiring professors involved in the SyDAD program I believe together we can benefit from each others help and knowledge, to even increase the research possibilities.
Objectives: We have recently identified a protein called adenylate cyclase-associated protein 2 (CAP2), which interacts with both actin and ADAM10 (cleaving APP, but also cell adhesion molecules) and preliminary data show that CAP2 binding to actin is essential for ADAM10 endocytosis.
The aims of the project are:
- To characterize the molecular determinant of ADAM10/CAP2/actin complex.
- To study the role of CAP2 in actin and ADAM10 dynamics, spine remodelling and in AD pathogenesis.
Expected Results: The characterization of a new molecular linker bridging spine remodelling alterations and amyloid cascade, thereby providing a new pharmacological target and elucidating the missing links between Aβ oligomers and spines dysfunction in AD
Planned secondments: Karolinska Institutet.
Read more about Ana and her project
I’m from Braga, a small city in the North of Portugal. I’ve started my academic life with a degree in Applied Biology and I’ve continued to a Master in Health Sciences, both held in University of Minho, in Braga.
I’ve applied to SyDAD as I thought it was a great program, with well-known supervisors and participating institutions and the projects seemed very interesting and within the actual panorama of research.
I will benefit from SyDAD as it provides me an outstanding opportunity to work with the great scientists in the field, working outside my own country and turning my PhD into an exciting work experience, with all the courses being held in different institutions and allowing me to get to know how science is done across Europe.
I believe that all of us are starting to make a difference (even if it’s small), as research in Alzheimer’s disease concerns a very well-known disease that affects millions nowadays and with the tendency to increase its numbers in the next few years. Research within its pathways, molecular alterations and possible treatments it’s crucial, so we are all working towards a better tomorrow.
Objectives: We have recently identified Ring Finger Protein 10 (RNF10) as a novel synapse-to-nucleus protein messenger that specifically links activation of synaptic GluN2A-containing NMDARs to nuclear gene expression.
The aims of the project are:
- to characterize RNF10 in Aβ signalling, by using RNF0 KO mice and
- to determine which genes are modulated by Aβ-driven RNF10 trafficking to the nucleus. A selected number of these genes will be exploited for rescue experiments.
Expected Results: The project will unravel the role of RNF10 in AD pathogenesis. In particular, we will identify genes that RNF10 modulates, which could represent potential novel AD pharmaceutical targets.
Planned secondments: DZNE, University of Bordeaux and Janssen Pharmaceuticals.
Read more about Sebastien and his project
I come from Grenoble a charming town in the French Alpes. I studied Psychology in the University of the Alpes. Afterwards, I moved to the University of Strasbourg where I completed a master’s degree in Cellular and integrative neuroscience.
I chose the SyDAD program because it is a highly competitive program with high level courses and trainings in top laboratories around Europe. It allows me to upgrade my research skills and expand my scientific knowledge. It is also a great chance to be in a stimulating context and meet international students and top research scientists in AD field.
Regarding my project, I was always interested in Alzheimer’s disease. Working on developing and testing a potential new therapeutic is very motivating. Such work will also provide great information about the molecular mechanisms involved in the pathology.
Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by progressive loss of synapses and neurons and accumulation of insoluble deposits of amyloid beta-peptide (Aβ). No cure is available at the moment and prevention or delay of Alzheimer’s disease onset is among the most urgent moral, social, economic and scientific imperatives in industrialized countries. Aβ derives from the amyloid precursor protein (APP), which can undergo 2 mutually exclusive pathways in the cell. The amyloidogenic pathway involves BACE and gamma secretase activities and leads to Aβ formation. On the other hand, the main protagonist of the non-amyloidogenic pathway is ADAM10, a disintegrin and metalloproteinase 10, which cleaves APP in the domain corresponding to Aβ, thus precluding Aβ production. Recently Prof Di Luca’s lab characterized the cellular mechanisms underlying ADAM10 removal from the plasma membrane. In particular, we have identified a new ADAM10 binding partner, named AP2, which is responsible for the ADAM10 internalization. Therefore, ADAM10/AP2 interaction modulates ADAM10 activity. Moreover ADAM10/AP2 interaction is significantly increased in AD patients’ brain compared to healthy control subjects, suggesting a role of ADAM10/AP2 in Alzheimer’s disease pathogenesis. Prof. Monica Di Luca’s lab has recently developed cell permeable peptides capable of interfering with ADAM10 endocytosis and I planned to design new peptidomimetics compound to improve the pharmacokinetics properties. The aim of this project is to rescue Alzheimer’s disease phenotype by administration of such compounds to Alzheimer’s disease transgenic mice.
Axon Neuroscience (Bratislava, Slovakia): To study the efficacy of Cell Permeable Peptides in animal models of Tau dysfunction.
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
Read more about Sara and her project
My name is Sara Rodrigues and I´m from Portugal. I did a BSc in Applied Biology and MSc in Health Sciences – Neurosciences in the University of Minho, Portugal.
I applied to the SYDAD program because I wanted to continue developing my scientific career in the field of Alzheimer’s disease. SYDAD presents an excellent training program, in an innovative and collaborative basis, also offering the possibility of international exchanges between the partner organizations. The interaction and collaboration between academia, pharmaceutical companies and the clinics, along with the high quality of the institutions involved, are certainly a great benefit for the ESRs.
With my research I hope to contribute to the dissemination and recognition of the SYDAD program, as well as to find therapeutic targets to prevent or halt the progression of Alzheimer’s disease, which would produce a massive social and economic impact.
Objectives: In AD, Tau pathology spreads in a progressive and stereotypical fashion, with Tau inclusions developing in a well-defined predictable manner. Several models have been proposed to explain this phenomenon, for example a prion-like mechanism which involves the transfer of misfolded Tau between cells and templated assembly of cellular Tau.
To study the progression of Tau pathology we will make use of novel combinations of methods to model Tau-dependent neurodegeneration in mice (regulatable, region-specific promoters, local AAV-based challenges by Tau, testing of novel FTD-related mutants of Tau).
Expected results: identification of the mechanisms underlying the spreading of Tau pathology and the functional roles of different Tau strains.
- Daniele Bano (DZNE): Functional roles of Tau phosphorylation in animal models
- Juan D. Pita Almenar (JPNV): Mechanisms of spreading of Tau pathology
Read more about Anaïs and her project
My name is Anaïs Marsal and I come from Arbeca, Spain. I obtained my Bachelor’s degree in Biochemistry and Molecular Biology at the University Rovira and Virgili in Spain. During the undergraduate program I participated as a Junior Specialist in one of the research projects on AD of Tenner ́s Lab, from the University of California at Irvine. With this experience along with other internships I created even more passion to focus on Neurosciences. Thus, I performed my Master in the School of Medicine from the University of Barcelona.
I want to focus my career on neurodegeneration in Alzheimer’s Disease because I want to contribute to the understanding and investigation of this exciting topic for me, which may help to improve people’s life and ageing. I decided to apply for the SyDAD project because it provides an excellent and well-structured training program, focusing on investigating the cross-talk between different pathways underlying synaptic dysfunction in AD and aiming to identify novel pharmaceutical targets.
Impaired mitochondrial function is associated with AD and likely contributes to the onset and progression of the pathology. Previous work conducted in the laboratory of Dr. Bano showed alterations of certain metabolic and signaling pathways due to mitochondrial deficiency. By working on nematode and cellular models of mitochondrial deficiency we will aim to ameliorate these alterations both through genetic and pharmacological interventions. Ultimately we will attempt to investigate the role of this global metabolic rewiring as well of our interventions on aberrant Tau function.
Read more about Fabio and his project
Originally from Alto Adige (Südtirol), an Italian region in the Alps, I lived in Padova where I studied Pharmaceutical Biotechnologies. Thanks to my scientific working experience I have understood that I’m fascinated by neuroscience and more specifically by AD. Therefore, SyDAD was just the perfect program to apply to, to have the possibility to deepen my interest in a stimulating and international environment. With this program I expect to grow scientifically and personally with the aim to become an independent scientist and a complete worker. Moreover with my project I hope to contribute to a small enlargement of our scientific knowledge of brain processes, which in my opinion is one of the biggest challenges of the human being.
Objectives: Amplification of Ca2+ signaling at synapses is at the basis of memory processes by dendritic and synaptic remodeling. We have therefore generated transgenic mice lacking RyR2 (regulating Ca2+ release from ER) in specific areas of the brain.
- To determine the relevance of calcium remodeling in learning and memory paradigms
- To quantify alterations of the synaptic compartment in RyR2 deficient mice.
- To assess possible changes of Tau modification and APP processing in RyR2 deficient animals.
- Elucidation of the role of Ca2+ remodelling on synaptic dysfunction and links to tau and Aβ.
Planned secondments: University of Milano and Karolinska Institutet
Janssen Pharmaceutica NV, Beerse, Belgium
Read more about Miguel and his project
My name is Miguel Matias, I am Portuguese and I did my Bachelor in Biochemistry and Master degree in Celullar Molecular Biology in the University of Coimbra. During my second year of master’s degree, I went to Bordeaux, where I did my master thesis on receptor surface dynamics utilizing super-resolution microscopy. I applied to the SyDAD program because it was focused on my exact two interests in neuroscience: synaptic plasticity and Alzheimer’s disease. Besides that, the international nature of the program was very appealing, as it would provide travel opportunities and meeting new people. By enrolling in this program, and under the guidance of the various experts in the field, I expect to become skilled in synaptic (dys)function in AD, to contact with different investigators, techniques and expertise across the different laboratories and to create a network of contacts that will, for sure, be valuable in the future. Hopefully, by the end of my path in SyDAD, my findings will prove useful for a better and more complete understanding of AD pathology and ultimately aid in the treatment of this devastating disease.
Rationale: Accumulation and spreading of neurofibrillary tangles of hyperphosphorylated tau has been extensively linked to the onset and progression of Alzheimer’s disease. Even though synapse dysfunction and synaptic loss are known to underlie the cognitive decline which is characteristic of Alzheimer’s disease, the direct effect that spreading of tau pathology has on synaptic function remains unclear. Recent studies have shown that intracerebral injections of preformed tau fibrils into different brain regions of young mice expressing mutant human tau (P301L) induces tau hyperphosphorylation, aggregation, and a time-dependent propagation of tau pathology to interconnected brain regions (Peeraer et al., 2015). This unique tau seeding model gives us the opportunity to investigate how the spreading of tau pathology alters normal functioning of synaptic transmission during the progression of the disease.
- To perform a spatio-temporal analysis of synaptic function during the progression of tau pathology: Using slice elctrophyisiology we will investigate alterations in synaptic transmission and synaptic plasticity during the spread of tau pathology triggered after seeding tau aggregates.
- To perform a spatio-temporal analysis of synaptic structures during the progression of tau pathology: Using high content structural imaging we will investigate alterations in dendritic spines and synaptic terminal morphology in animals where tau aggregate dependent neuronal loss is triggered after seeding.
Expected Results: We expect to identify tau-aggregation induced phenotypes at the functional level (using electrophysiology) and the morphological level (high content structural imaging) that will help us understand the role of tau in AD pathogenesis. Developed methods and findings will support development of compounds or antibodies aimed to treat AD.
Planned Secondment: University of Bordeaux, 2018-2019
Axon Neuroscience, Bratislava, Slovakia
Read more about Thomas and his project
My name is Thomas Vogels from The Netherlands. I did my research master Neuroscience at VU University Amsterdam, during which I gained further research experience at University of Oxford and Janssen Pharmaceuticals. I applied to SyDAD because I wanted to work on a topic with great societal importance from a systems neuroscience perspective. I’m very excited to be part of the SyDAD network, because it allows me to meet new people, collaborate with excellent researchers in the field, work in international labs and receive training in various places all over Europe. The goal of my research is to explain how tau-mediated synaptic dysfunction affects neuronal circuits and leads to the cognitive symptoms seen in Alzheimer’s disease. Studying how novel treatments for Alzheimer’s disease affect synaptic and neuronal network dysfunction will hopefully lead to better predictions of clinical outcomes in patients.
Previous research shows that the pathological function of tau protein leads to dysfunction and loss of the connections between neurons in Alzheimer’s disease, a process which is closely linked to cognitive decline in patients. Tau protein can be cut at several sites, which causes changes in its structural and functional properties. Currently, very little is known about how these tau fragments lead to synaptic dysfunction and interact with other aspects of the disease. We will use in vivo 2-photon calcium imaging to study the functions of defined neuronal populations in the neocortex. We will then study the relationship between tau pathology and synaptic dysfunction in the previously recorded neurons. Furthermore, we hope to rescue these synaptic and neuronal network abnormalities with tau-based immunotherapeutics. The ultimate goal of my project is to provide more insight into the role of tau-mediated synaptic dysfunction, which will lead to better prediction of clinical outcomes in patients with Alzheimer’s disease.
Planned secondments: University of Bordeaux