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P13. Neuronet: From risk, to dementia – Understanding disease progression and its causes

Detailed programme, abstracts and poster presentations

P13.1. María Eugenia Sáez (Spain): ADAPTED - Alzheimer's disease apolipoprotein pathology for treatment elucidation and development

María Eugenia Sáez

Spain

Background: The ADAPTED (Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development) project is a joint initiative aimed at improving the understanding of the function of the APOE gene, a well-known risk factor for developing Alzheimer’s (AD) disease by unknown pathological mechanisms.

Methods: ADAPTED has established relevant human cell models to enable the systematic investigation of APOE biology by cell reprogramming, genome editing and differentiation of cells from AD patients and healthy controls to create a set of relevant cell-types (astrocytes, neurons, macrophages and microglia). The role of APOE it is also being investigated using blood and cerebrospinal fluid (CSF) from AD patients, controls and subjects with mild cognitive impairment (MCI). In addition, ADAPTED researchers have collected multi-omics publicly available datasets that have been explored for APOE pathogenic mechanism.

Results: Integration of the different sources of information during the project points to a pivotal role of immune system in the development of AD, showing both APOE and cell specific signatures.

Conclusion: The tools generated by ADAPTED allows to explore phenotypic effects of APOE alleles in key target cells. These methods have already led to the identification of relevant immunological pathways that are being further explored by the ADAPTED consortium researchers.

P13.2. PHAGO - Targeting TREM2 and CD33 of phagocytes for treatment of Alzheimer’s disease

HODGES Angela

United Kingdom

“Alzheimer’s disease (AD) is an age-related chronic neurodegenerative disease with progressive loss of nerve cells and their connectivity in the brain. Today, over 46 million people live with dementia worldwide and this number is estimated to increase to 131.5 million by 2050. Phagocytes accumulate around amyloid plaques in the brains of AD patients and show a dysfunctional activation profile. Genetic approaches have identified two innate immune receptor genes TREM2 and CD33/SIGLEC3 as disease relevant players in AD. These findings present novel and attractive targets for treatment. However, their exact role and underlying cellular mechanisms are still unclear.

PHAGO aims to fill this knowledge gap and provide tools and assays for targeting these innate immune receptors, namely TREM2 and CD33/SIGLEC3, which might help to pave the way for new therapeutic strategies for AD, in a collaboration between academia and industry under the Innovative Medicines Initiative (IMI 2 JU No 115976). 

So far, PHAGO has succeeded in developing and establishing a range of highly valuable tools, such as novel animal models for TREM2 mutations (Xinag et al, 2018), the first set of isogenic iPSC lines of TREM2/CD33 variants that will be further expanded (Garcia-Reitboeck et al 2018, plus unpublished available through EBiSC2) and cellular TREM2 and CD33 reporter systems to allow a first pilot screening attempt (Carillo-Jiminez et al, 2018). Furthermore, one of several systematic analyses of transcriptome data on PHAGO’s bespoke knowledge and omics platform has described that loss of TREM2 in microglia leads to widespread disruption of cell coexpression networks in mouse brain (Carbajosa et al. 2018). The CD33 crystal structure complexed with sialic acid derivatives has been resolved (Miles et al, 2019) to eventually support rational drug design.

The PHAGO consortium is also interacting with other IMI-collaborative undertakings in order to maximally utilize synergisms throughout the European Research landscape, e.g. in bioinformatics (IMI ADAPTED), iPSC (IMI EBiSC2) and animal models of tauopathy (IMI IMPRiND).”

P13.3. AETIONOMY - Organising mechanistic knowledge about neurodegenerative diseases for the improvement of drug development and therapy

HOFMANN-APITIUS Martin1, SCHNEIDER Reinhard2, FORGÓ Nikolaus3, CORVOL Jean-Christophe4, CARNARD Luc5, FRÖHLICH Holger6, SCORDIS Phil7 and the AETIONOMY consortium 

1Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Sankt Augustin, Germany, 2Université du Luxembourg, Belvaux, Luxembourg, 3University of Vienna, Vienna, Austria, 4Institut du Cerveau et de la Moelle (ICM), Paris, France, 5Sanofi, Chilly-Mazain CEDEX, France, 6UCB BioPharma, Monheim, Germany, 7UCB BioPharma, Slough, United Kingdom

The AETIONOMY project was initiated to pave the way for a “mechanism-based taxonomy for neurodegenerative diseases”. The generation of such a “mechanism-based taxonomy” is an extremely ambitious undertaking, as neurodegenerative diseases are widely known as “idiopathic diseases”, which means that the disease etiology is unknown.

Over the project runtime of 5 years, the AETIONOMY consortium has implemented a big data approach that delivered not only the proof-of-concept that a mechanism-based taxonomy for neurodegenerative diseases is possible, but also a broad spectrum of resources, which are of highest value for ongoing and future research on neurodegeneration. AETIONOMY has generated the largest inventory of knowledge-based, computable disease mechanism representations for Alzheimer´s disease and Parkinsonism worldwide. It has furthermore developed the text analytics machinery to keep these computable models of disease up to date. Moreover, in the course of the project we developed the algorithmic basis for modeling and mining that associates disease mechanisms with (longitudinal) patient-level data. All these resources were made freely accessible and usable to the scientific community. The clinical work package has recruited its own Parkinsonism – cohort and in close collaboration between data scientists and clinical researchers, we could demonstrate that defined candidate mechanism have the potential to identify patient subgroups in this cohort and an independent control cohort.

AETIONOMY has paved the way for future stratification of patients according to underlying disease mechanisms (or combination of disease mechanisms). As the first project of this kind, AETIONOMY has successfully demonstrated that an approach that tries to make all public knowledge and all public data in a given indication area interoperable and amenable for modeling and mining, is possible.

More than that: AETIONOMY has also shown that the substantial investment in this effort is well justified, as it leads to meaningful results

 

 
 

Last Updated: Friday 18 October 2019

 

 
  • Acknowledgements

    The 29th AE Conference in The Hague received funding under an operating grant from the European Union’s Health Programme (2014-2020). Alzheimer Europe and Alzheimer Nederlands gratefully acknowledge the support of all conference sponsors.
  • European Union
  • Roche
 
 

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