The TAME project and the training programme it offers are funded under Horizon Europe’s Marie Skłodowska-Curie Actions (MSCA) programme.
TAME Training
TAME research programme
TAME offers a dedicated joint research programme in the diagnosis and treatment of tauopathies, anchored on Nanobody-based immune approaches targeting tau. Specialist training is obtained by attending training schools and other networking activities and through cutting-edge research projects. These individual projects will be supervised by TAME investigators that are internationally established top scientists in multiple fields.
This fosters close interaction with academic, clinical and entrepreneurial experts and provides a uniquely broad and inspiring palette of experiences to TAME’s fellows. This is complemented by the training on generic research and transferable skills.
The structure of TAME research training rests upon three complementary workpackages. We anticipate that the effort will be sustained by dissemination, communication and exploitation of the scientific outcomes to establish a long-term tau network, amplify research in the field and provide visibility for TAME research outcomes to various audiences. Some activities will also create a spectrum of new opportunities for innovation-driven companies resulting into new products for therapies and diagnosis in Alzheimer’s Disease and related pathologies benefiting society. We plan to enhance our chances of success by a highly selective recruitment of very talented fellows.
The structure of TAME research training rests upon three complementary workpackages. We anticipate that the effort will be sustained by dissemination, communication and exploitation of the scientific outcomes to establish a long-term tau network, amplify research in the field and provide visibility for TAME research outcomes to various audiences. Some activities will also create a spectrum of new opportunities for innovation-driven companies resulting into new products for therapies and diagnosis in Alzheimer’s Disease and related pathologies benefiting society. We plan to enhance our chances of success by a highly selective recruitment of very talented fellows.
The fellows
The training
Discover our WP
WP2 - Building technology
3 fellows develop technologies to detect specific tau species in biological fluids with highly sensitive, robust and reproducible measures or will optimise and functionalise tau-specific single-domain antibodies using chemical and genetic engineering to improve their properties and/or target neurons in the brain.
Institution :
Host : Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Supervisor : C. P. R. HACKENBERGER
Project :
Nbs from this network will be modified by advanced protein synthesis techniques available at FMP. In principle, we use expressed protein ligation (intein expression and native chemical ligation) for the C-terminal modification and Cys-selective conjugation reactions based on newly generated Cysteine-selective electrophiles for the labelling of Nbs. These Nb-bioconjugates are proposed to contain cell-penetrating peptides (CPPs), which, together with CPP-additives, render the Nbs cell-permeable and ensure an intracellular cleavage of the cell-permeation tag.
In addition, FMP will contribute its expertise in the field of tau synthesis to the synthesis of homogeneously phosphorylated and acetylated tau peptides and proteins for Nb screening.
Objectives :
Secondments :
Host : Hybrigenics Services
Project : Screen of Nb library with synthetic phosphorylated tau.
Supervisor : J-C. RAIN
Host : University of Liège
Project : Evaluation of cell-permeable P-tau Nbs in brain tissue
Supervisor : M. DUMOULIN
Host : Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Supervisor : C. P. R. HACKENBERGER
Project :
Nbs from this network will be modified by advanced protein synthesis techniques available at FMP. In principle, we use expressed protein ligation (intein expression and native chemical ligation) for the C-terminal modification and Cys-selective conjugation reactions based on newly generated Cysteine-selective electrophiles for the labelling of Nbs. These Nb-bioconjugates are proposed to contain cell-penetrating peptides (CPPs), which, together with CPP-additives, render the Nbs cell-permeable and ensure an intracellular cleavage of the cell-permeation tag.
In addition, FMP will contribute its expertise in the field of tau synthesis to the synthesis of homogeneously phosphorylated and acetylated tau peptides and proteins for Nb screening.
Objectives :
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- Deliver cell-permeable Nbs and labelled-Nbs.
- Use Cystein-selective probes as modular coupling reagents to be implemented in other laboratories in this network
Secondments :
Host : Hybrigenics Services
Project : Screen of Nb library with synthetic phosphorylated tau.
Supervisor : J-C. RAIN
Host : University of Liège
Project : Evaluation of cell-permeable P-tau Nbs in brain tissue
Supervisor : M. DUMOULIN
Institution :
Host : Hybrigenics Services
Supervisors : J-C RAIN & I. LANDRIEU
Project :
The project aims to develop strategies for the selection of bi-paratopic nanobodies (meaning two linked nanobodies that recognize two distinct sequences within the same protein or two distinct proteins)- or diabodies- using phage or yeast display and/or yeast two Hybrid to select the optimal linker to fit two validated Nbs. This project will be applied to the development of diabodies targeting both pro-aggregative regions of Tau. In addition, we will develop diabodies that will recognize a tau epitope and the transferrin receptor (tfR) to facilitate targeting of the active nanobody to the brain by facilitating the blood brain barrier crossing. We expect that the technologies and concepts develop during this project will have a broad application in particular on development of new bi-paratopic nanobodies e.g. that could recognize specific and distinct post translational modifications for a given antigen (a single protein).
Objectives :
Secondments :
Host : Consejo Superior de Investigaciones Científicas
Project : Use of diabodies in development of a multiplexed diagnostic platform
Supervisor : M-P. Marco
Host : Biomedical Sciences Research Centre “Alexander Fleming”
Project : Assays of diabodies against aggregated tau in Drosophila tauopathy model
Supervisor : E. Skoulakis
Host : Hybrigenics Services
Supervisors : J-C RAIN & I. LANDRIEU
Project :
The project aims to develop strategies for the selection of bi-paratopic nanobodies (meaning two linked nanobodies that recognize two distinct sequences within the same protein or two distinct proteins)- or diabodies- using phage or yeast display and/or yeast two Hybrid to select the optimal linker to fit two validated Nbs. This project will be applied to the development of diabodies targeting both pro-aggregative regions of Tau. In addition, we will develop diabodies that will recognize a tau epitope and the transferrin receptor (tfR) to facilitate targeting of the active nanobody to the brain by facilitating the blood brain barrier crossing. We expect that the technologies and concepts develop during this project will have a broad application in particular on development of new bi-paratopic nanobodies e.g. that could recognize specific and distinct post translational modifications for a given antigen (a single protein).
Objectives :
- Preparation of recombinant aggregated tau & phosphorylated P-tau for Nb screening assays;
- Implement a new selection method using yeast display and/or yeast two Hybrid to select the optimal linker to fit two validated Nbs as bi-epitopic diabodies or a validated tau-specific Nb with a tfR specific Nb as bi-specific diabodies;
- Implement new selection process inside yeast to select best pair of validated Nbs for split nanoluc diagnostic development assay;
- Identify by phage and yeast display new sets of Nbs specifically recognising aggregated tau & P-tau forms;
- Optimize Nbs for affinity or intracellular activity using Y2H or yeast display.
Secondments :
Host : Consejo Superior de Investigaciones Científicas
Project : Use of diabodies in development of a multiplexed diagnostic platform
Supervisor : M-P. Marco
Host : Biomedical Sciences Research Centre “Alexander Fleming”
Project : Assays of diabodies against aggregated tau in Drosophila tauopathy model
Supervisor : E. Skoulakis
Institution :
Host : Spanish National Research Council CSIC
Supervisors : M-P MARCO & J-P SALVADOR
Project :
The candidate will be enrolled in the Nanobiotechnology for Diagnostics group aiming at the development of nanobodies with specific biorecognition profile against peptides from TAU protein. The implication of the early stage scientist (ESR) will be crucial for accomplishing the specific objectives proposed. The ESR will join the Nb4D group under the supervision of Dr. J.-Pablo Salvador and Prof. M.-Pilar Marco, both in charge of the correct development of the project and PhD thesis of the student. The candidate will be involved in the PhD Biotechnology program from University of Barcelona. The candidate will be part of the actively scientific routine of the group, joining the scientific seminars, attending to national/international workshops and conferences and taking courses both on specific matters related to the project activities.
Objectives :
Secondments :
Host : Hybrigenics Services
Project : Optimisation of tau-specific Nb & diabody affinity.
Supervisor : J-C RAIN
Host : Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Project : Modification for cell penetration affinity.
Supervisor : C. HACKENBERGER
Host : VU University Medical center Amsterdam
Project : Assessment of the clinical value of the multiplexed IVD platform
Supervisor : C. TEUNISSEN
Host : Spanish National Research Council CSIC
Supervisors : M-P MARCO & J-P SALVADOR
Project :
The candidate will be enrolled in the Nanobiotechnology for Diagnostics group aiming at the development of nanobodies with specific biorecognition profile against peptides from TAU protein. The implication of the early stage scientist (ESR) will be crucial for accomplishing the specific objectives proposed. The ESR will join the Nb4D group under the supervision of Dr. J.-Pablo Salvador and Prof. M.-Pilar Marco, both in charge of the correct development of the project and PhD thesis of the student. The candidate will be involved in the PhD Biotechnology program from University of Barcelona. The candidate will be part of the actively scientific routine of the group, joining the scientific seminars, attending to national/international workshops and conferences and taking courses both on specific matters related to the project activities.
Objectives :
- Design and synthesis of peptide haptens mimicking tau peptide epitopes resulting from PTM and N-terminal fragments;
- Accomplish a Nb panel recognising distinct PTMs and N-terminal fragments, using the above synthetic peptide fragments;
- Develop a multiplexed diagnostic platform for profiling tau species in body fluids;
- Chemometric and data analysis studies to interpret results of the multiplexed platform;
- Implement the technology to analyse body fluids from biobanks.
Secondments :
Host : Hybrigenics Services
Project : Optimisation of tau-specific Nb & diabody affinity.
Supervisor : J-C RAIN
Host : Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Project : Modification for cell penetration affinity.
Supervisor : C. HACKENBERGER
Host : VU University Medical center Amsterdam
Project : Assessment of the clinical value of the multiplexed IVD platform
Supervisor : C. TEUNISSEN
WP3 - Building knowledge
3 fellows link specific tau species to sex-specificity, stage & subtype of the pathology to personalise medicine: clarification of the tau species (PTMs, fiber conformations, isoforms and truncated forms) involvement to particular disease symptoms and manifestations.
Institution :
Host : Deeplife
Supervisors : J-B MORLOT & L. BUEE
Project :
Tauopathies are characterized by abnormal tau protein buildup in the brain, leading to the formation of filaments, obstructing nerve synapses, impacting cell viability thus leading to neurodegenerative disorders. DeepLife will use proprietary data obtained from cell cultures, in vivo models and open-access data to build a digital model of a neuron affected by tau pathology to predict novel biomarkers and therapeutic strategies. The objective of the PhD project will be on training large scale generative models, aka digital twins of cells, on an in-house curated single cell multi-omics database.
Objectives :
Secondments :
Host : Institut National de la Santé et de la recherche médicale
Project : Generation of omics data on human cells
Supervisor : I. LANDRIEU & L. BUEE
Host : Deeplife
Supervisors : J-B MORLOT & L. BUEE
Project :
Tauopathies are characterized by abnormal tau protein buildup in the brain, leading to the formation of filaments, obstructing nerve synapses, impacting cell viability thus leading to neurodegenerative disorders. DeepLife will use proprietary data obtained from cell cultures, in vivo models and open-access data to build a digital model of a neuron affected by tau pathology to predict novel biomarkers and therapeutic strategies. The objective of the PhD project will be on training large scale generative models, aka digital twins of cells, on an in-house curated single cell multi-omics database.
Objectives :
- Compile and harmonise multi-omics neuronal data-sets available on qualified repositories and from in-house experiments (INSERM) ;
- Build a Model of a digital neuronal cell ;
- Analyse pathway upon perturbation of the system by tau mutations based on in-house omics data ;
- Analyse biomarker prediction based on impacted pathways (e.g. specific kinase activations) ;
Secondments :
Host : Institut National de la Santé et de la recherche médicale
Project : Generation of omics data on human cells
Supervisor : I. LANDRIEU & L. BUEE
Institution :
Host : Biomedical Sciences Research Center “Alexander Fleming”
Supervisors : E. MC SKOULAKIS & K. PAPANIKOLOPOULOU
Project :
Nanobody mediated amelioration of aggregate formation, neuronal dysfunction and toxicity of Tau species. Use of specific anti-Tau nanobodies to identify potential Tauopathy biomarkers in biological fluids and tissues. Use of Drosophila and mouse models and patient samples as necessary.
Objectives :
Secondments :
Host : Instant NanoBiosensors Co.,Ltd.
Project : Evaluate specificity, stability and overall biophysical properties of Nb-tauP.
Supervisor : T-C CHANG
Host : University of Liège
Project : Design a bispecific Nb penetrating the BBB.
Supervisor : M. DUMOULIN
Host : Biomedical Sciences Research Center “Alexander Fleming”
Supervisors : E. MC SKOULAKIS & K. PAPANIKOLOPOULOU
Project :
Nanobody mediated amelioration of aggregate formation, neuronal dysfunction and toxicity of Tau species. Use of specific anti-Tau nanobodies to identify potential Tauopathy biomarkers in biological fluids and tissues. Use of Drosophila and mouse models and patient samples as necessary.
Objectives :
- Introduce Nanobodies to strains expressing the main pathogenic human wild type and mutant tau isoforms in Drosophila;
- Determine the effects of the transgenically expressed Nanobodies on the steady-state levels of tau in the fly CNS, the steady-state phosphorylation patterns & the aggregation levels;
- Determine the effect of Nanobody expression on the tau-dependent lethality/shortened lifespan, levels of oxidative stress, deficient learning and long-term memory. We plan to repeat these experiments with novel Nbs against two selected tau phosphorylation sites (pS238 & pS262);
- Evaluate memory gain in tauopathies mouse model (Davis mouse) expressing tau (or P-tau) Nbs using adeno-associated virus technology (AAV). We plan to assay 1-3 Nanobodies. Sex balance is considered in animal cohorts.
Secondments :
Host : Instant NanoBiosensors Co.,Ltd.
Project : Evaluate specificity, stability and overall biophysical properties of Nb-tauP.
Supervisor : T-C CHANG
Host : University of Liège
Project : Design a bispecific Nb penetrating the BBB.
Supervisor : M. DUMOULIN
Institution :
Host : Centre National de la Recherche Scientifique (CNRS)
Supervisors : I. LANDRIEU & L. BUEE
Project :
Our main objectives are to provide high-quality anti-tau nanobodies to assay their properties using biophysical or structural biology methods and to evaluate their therapeutic potential to define pathological tau species and their toxicity (capacity of seeding and spreading).
Objectives :
Secondments :
Host : VU University Medical center Amsterdam
Project : Damages associated to tau aggregation are evaluated in cell culture models.
Supervisor : C. TEUNISSEN
Host : Deeplife
Project : Cross-validate pathological tau species in digital model – integrate omics data to the model.
Supervisor : J.B MORLOT
Host : Centre National de la Recherche Scientifique (CNRS)
Supervisors : I. LANDRIEU & L. BUEE
Project :
Our main objectives are to provide high-quality anti-tau nanobodies to assay their properties using biophysical or structural biology methods and to evaluate their therapeutic potential to define pathological tau species and their toxicity (capacity of seeding and spreading).
Objectives :
- Evaluate the inhibition capacity of various nanobodies to block tau aggregation in in vitro assays and tau seeding in biosensor HEK cellular model;
- Analyze neuron-to-neuron transfer of tau in primary cells using microfluidic device assays with either lentiviral vectors or recombinant proteins. Analyses are mainly done by fluorescence microscopy;
- Detect pathological species of tau in brain slices of Alzheimer’s Desease with tau-specific nanobodies. Analyses is done by fluorescence microscopy (confocal, spinning disk);
- Obtain omics data on miNs culture (at 30 days) obtained from reprogramming fibroblasts of patients (Lille Hospital) with tau P301S and tau P332S congenital mutations. Control is derived from fibroblasts of healthy patients. Sex balance is considered in fibroblasts collection.
Secondments :
Host : VU University Medical center Amsterdam
Project : Damages associated to tau aggregation are evaluated in cell culture models.
Supervisor : C. TEUNISSEN
Host : Deeplife
Project : Cross-validate pathological tau species in digital model – integrate omics data to the model.
Supervisor : J.B MORLOT
WP4 - Evaluate clinical interest
3 fellows define the clinical value of the engineered tau-specific single-domain antibodies to detect pathological tau species in the living brain (by PET imaging) and in biological fluids and determine single-domain antibody-mediated modulation of pathological tau.
Institution :
Host : University of Gothenburg
Supervisor(s) : H. ZETTERBERG, L. MONTOLIU-GAYA & N. ASHTON
Project :
The aim of the project is to develop novel sandwich assays using the tau Nbs generated in the project. The PhD student will develop digital ELISAs using Single Molecule Array (Simoa) analysers and perform analytical and clinical evaluation and validation of the developed immunochemical technologies.
Objectives :
Secondments :
Host : Consejo Superior de Investigaciones Científicas
Project : Use bioinformatics to generate new diabody against specific tau epitope combinations.
Supervisor : M-P. MARCO
Host : Hybrigenics Services
Project : Library screening for Nbs against aggregated tau.
Supervisor : J-C. RAIN
Host : University of Gothenburg
Supervisor(s) : H. ZETTERBERG, L. MONTOLIU-GAYA & N. ASHTON
Project :
The aim of the project is to develop novel sandwich assays using the tau Nbs generated in the project. The PhD student will develop digital ELISAs using Single Molecule Array (Simoa) analysers and perform analytical and clinical evaluation and validation of the developed immunochemical technologies.
Objectives :
- Developing digital ELISAs using single molecule array (Simoa) analyzers;
- Analytical and clinical evaluation and validation of the immunochemical technologies developed.
Secondments :
Host : Consejo Superior de Investigaciones Científicas
Project : Use bioinformatics to generate new diabody against specific tau epitope combinations.
Supervisor : M-P. MARCO
Host : Hybrigenics Services
Project : Library screening for Nbs against aggregated tau.
Supervisor : J-C. RAIN
Institution :
Host : Amsterdam University Medical Centers
Supervisors : C. TEUNISSEN, I. VERBERK, J. HOOZEMANS & W. SCHEPER
Project : The aim of the project is to develop and validate immunoassays using tau-specific nanobodies, using state of the art technologies, such as Ella, Simoa and Nanobiosensors. Successful assays will be used to define their use in clinical patient care, by validation in well-characteristed biobanked body fluid samples (applying regression statistics) and tissue samples. Furthermore, the role of these isoforms in tau aggregation in vitro will be studied using these tools.
Objectives :
Secondments :
Host : University of Gothenburg
Project : Validation of the developed biomarker and in vitro results using mass spectrometry.
Supervisor : H. ZETTERBERG
Host : Instant NanoBiosensors Co., Ltd.
Project : develop a biosensor to detect tau biomarkers using functionalised nanogold particles and optical fibre to detect with high sensitivity particle plasmon resonance .
Supervisor : T-C CHANG
Host : Amsterdam University Medical Centers
Supervisors : C. TEUNISSEN, I. VERBERK, J. HOOZEMANS & W. SCHEPER
Project : The aim of the project is to develop and validate immunoassays using tau-specific nanobodies, using state of the art technologies, such as Ella, Simoa and Nanobiosensors. Successful assays will be used to define their use in clinical patient care, by validation in well-characteristed biobanked body fluid samples (applying regression statistics) and tissue samples. Furthermore, the role of these isoforms in tau aggregation in vitro will be studied using these tools.
Objectives :
-
- Develop immunoassays using Nbs to detect tau species in body fluids such as CSF and blood. To optimise the assays for detection in brain tissue homogenates of tauopathy patients;
- Validate the assays analytically, and clinically in patients with tauopathies, such as AD and FTD. First proof of concept will be provided in cohorts of n=20 per group. If successful, assays will be further optimised and clinically validated in larger patient samples. Sex balance is considered in human cohorts;
- Validate the use of the novel detection tools and Nbs in brain tissue of patients with tauopathies;
- Damages associated to tau aggregation are evaluated in cell culture models.
Secondments :
Host : University of Gothenburg
Project : Validation of the developed biomarker and in vitro results using mass spectrometry.
Supervisor : H. ZETTERBERG
Host : Instant NanoBiosensors Co., Ltd.
Project : develop a biosensor to detect tau biomarkers using functionalised nanogold particles and optical fibre to detect with high sensitivity particle plasmon resonance .
Supervisor : T-C CHANG
Institution :
Host : University of Liège
Supervisors : M.DUMOULIN, P. MAQUET & T. GENDRON
Project :
Our main objective is to develop a PET imaging tracer for highly specific and sensitive detection and quantification of pathological Tau protein in the brain of AD transgenic mice models.
Objectives :
Secondments :
Host : Biomedical Sciences Research Center “Alexander Fleming” – Institute for Fundamental Biomedical Research
Project : Use mouse model to assay brain delivery.
Supervisor : E. MC SKOULAKIS & K. PAPANIKOLOPOULOU
Host : DeepLife
Project :Cross-validate intraneuronal tau markers with digital models.
Supervisor : J-B MORLOT
Host : University of Liège
Supervisors : M.DUMOULIN, P. MAQUET & T. GENDRON
Project :
Our main objective is to develop a PET imaging tracer for highly specific and sensitive detection and quantification of pathological Tau protein in the brain of AD transgenic mice models.
Objectives :
- Select the Nb (Nb-tauP, a Nb targeting a phosphorylated tau epitope) that diffuses the best into the brain and label neurofibrillary tangles following intra intracerebral injection. Fuse, by genetic engineering, Nb-tauP to cell-penetrating peptides and to Nbs known to increase BBB-passage by transcytosis (anti‐transferrin receptor-TfR). Bispecific Nbs and packaged Nb-tauP in protein capsule (NEU);
- Label the Nb-tauP and their functionalised version with 18-F;
- Investigate different routes of injection of 18F-Nb-tauP on its ability to cross the BBB;
- Carry out in vivo 18F-PET imaging using the best Nb-tauP-based functionalised Nb and the best delivery route of Nb-Tau in ThyTau22 mice model. Sex balance is considered in animal cohorts;
Secondments :
Host : Biomedical Sciences Research Center “Alexander Fleming” – Institute for Fundamental Biomedical Research
Project : Use mouse model to assay brain delivery.
Supervisor : E. MC SKOULAKIS & K. PAPANIKOLOPOULOU
Host : DeepLife
Project :Cross-validate intraneuronal tau markers with digital models.
Supervisor : J-B MORLOT
