Clumps of proteins in the brain called amyloid plaques are a hallmark of Alzheimer’s disease, and very often specialised immune cells cluster around these plaques. Recent research has shown that two genes involved in the immune system, TREM2 and CD33, appear to be involved in this immune response to Alzheimer’s disease and could therefore be targets for drugs. However, their exact role in the disease is still poorly understood. The PHAGO project aims to develop tools and methods to study the workings of these genes. The project results will therefore pave the way for the development of novel drugs that could tackle Alzheimer’s disease via this route.
FACTS & FIGURES
IMI2 - Call 5
|Grant agreement number
Type of Action:
8 838 000
|EFPIA in kind
9 445 395
18 221 231
Achievements & News
PHAGO partner looks to patent new culturing technique for deriving microglia from stem cells
An SME partner in the IMI PHAGO project has filed a patent application with the European Patent Office for an improved protocol for generating high numbers of human microglia, implicated in Alzheimer’s disease, from induced pluripotent stem cells (iPSCs).###
Microglia are thought to play an important role in the development and progression of Alzheimer’s. To understand more about their function, researchers in PHAGO looked at genetically distinct iPSCs generated from the blood of patients with Alzheimer’s, and microglia derived from them. This technique is technically challenging and cumbersome.
LIFE & BRAIN GmbH, who is co-leading the project’s work package on iPSC models, has now developed an improved method that involves new types of material, using patient cells collected by the team at King's College London. The new method enables bioreactor-based expansion and can yield very high numbers of iPSC-derived microglia.
This technique not only facilitates biomedical research; it might also offer new perspectives for a possible immunotherapeutic approach to treat patients with a genetic disposition to Alzheimer’s. In the PHAGO project, 40 iPSC lines have already been generated from donors that carry several different genetic mutations in the TREM2 or CD33 gene. PHAGO is working with the IMI initiative EBiSC (European Bank for Induced pluripotent Stem Cells) to make these cell lines accessible to researchers via the EBiSC catalogue.
Note: this article was corrected on 5 June - the cells lines are not yet accessible via the EBiSC catalogue, but EBiSC and PHAGO are working together to make this possible.
PHAGO reveals complex role of TREM2 gene in Alzheimer’s disease
Scientists have shed new light on how a gene called TREM2 influences the progression of Alzheimer’s disease in different ways in the early and later stages. The findings, published in Nature Neuroscience, add to our understanding of the disease and have major implications for drug development. ###The work was funded in part by IMI through the PHAGO project. TREM2 codes for the TREM2 protein, which activates immune cells in the brain called microglia. Microglia play a vital role in the removal of amyloid plaques, the tangled toxic proteins which are a hallmark of Alzheimer’s disease. In this study, the researchers showed that in mice with early signs of plaque deposition (and a functioning TREM2 gene), microglia cluster around small plaques and cause them to disintegrate. In mice lacking a functional TREM2 gene, the microglia were not able to break up the amyloid plaques. This suggests that in early stage Alzheimer’s disease, activating TREM2 could help to prevent the build-up of toxic amyloid plaques.
However, the results of a similar test in mice with more advanced plaque deposition paint a different picture. There, the amyloid plaques grew faster in mice with a functioning TREM2 gene than in mice without it. Further analyses showed that in the microglia, TREM2 also stimulates the production of a protein called ApoE, which is by far the strongest genetic risk factor for developing sporadic Alzheimer’s disease, and is thought to promote the aggregation of amyloid plaques. ‘Our findings indicate that future therapies will need to be applied in a stage-specific manner,’ says Christian Haass of DZNE Munich and Ludwig-Maximilians University, who led the research. ‘Based on the outcome of our study, activation of microglia by TREM2 would be a useful strategy to apply during the early phase of the condition.’ Professor Haass and his colleagues are now working on antibodies that could stabilise the TREM2 protein, increasing its ability to activate microglia.
Participants Show participants on map
- Abbvie Deutschland GMBH & Co Kg, Wiesbaden, Germany
- Astrazeneca AB, Södertälje, Sweden
- Eisai Limited, Hatfield, United Kingdom
- Eli Lilly And Company LTD, Basingstoke, United Kingdom
- F. Hoffmann-La Roche AG, Basel, Switzerland
- H. Lundbeck As, Valby, Denmark
- Janssen Pharmaceutica Nv, Beerse, Belgium
- Sanofi-Aventis Recherche & Developpement, Chilly Mazarin, France
Universities, research organisations, public bodies, non-profit groups
- Charite - Universitaetsmedizin Berlin, Berlin, Germany
- Deutsches Zentrum Fur Neurodegenerative Erkrankungen Ev, Bonn, Germany
- Fraunhofer Gesellschaft Zur Forderung Der Angewandten Forschung Ev, München, Germany
- Goeteborgs Universitet, Gothenburg, Sweden
- King'S College London, London, United Kingdom
- Universitatsklinikum Bonn, Bonn, Germany
- University College London, London, United Kingdom
- University of Cambridge, Cambridge, United Kingdom
Small and medium-sized enterprises (SMEs) and mid-sized companies (<€500 m turnover)
- Arttic, Paris, France
- Axxam S.A, Bresso (Milan), Italy
- Life And Brain GMBH, Bonn, Germany
- Arttic Innovation GMBH, Munchen, Germany
|IMI funding in €
|Charite - Universitaetsmedizin Berlin
|Deutsches Zentrum Fur Neurodegenerative Erkrankungen Ev
|1 027 500
|Fraunhofer Gesellschaft Zur Forderung Der Angewandten Forschung Ev
|King'S College London
|1 115 000
|Life And Brain GMBH
|1 754 200
|University College London
|University of Cambridge
|1 052 500
|IMI funding in €
|Arttic Innovation GMBH
|8 838 000