Community Research and Development Information Service - CORDIS



Project ID: 305299
Funded under: FP7-HEALTH
Country: France


Project Context and Objectives:
In spite of valuable approaches applied to get a broad understanding of genetic, epidemiologic and molecular and system-level biological principles of human aging, cognitive decline remains as one of the greatest health challenges of the old age, with nearly 50% of adults over 85 who suffer from neurodegenerative diseases such as Alzheimer’s. Furthermore, drug development has not performed as expected in clinical trials, at least in part because of an insufficient mechanistic understanding at the systemic level in human.
AgedBrainSYSBIO is a timely and straightforward project based on the integration of available transcriptomics, proteomics and metabolomics data, addition of relevant novel sets of data, their modeling and experimental testing in both human, mouse and drosophila.
AgedBrainSYSBIO researchers study brain ageing, using multiple-level approaches such as systems biology based on large sets of data from ageing mammals and humans in normal situations and in pathological context such as Late-Onset Alzheimer Disease (LOAD) , protein-protein interactions, novel drosophila and mouse models based on molecular engineering, human neurons generated from cells isolated from patients with LOAD or control, engineered antibodies (intrabodies) directed against abnormal protein-protein interactions that may participate to the evolution of an abnormal ageing and whole-genome data(Genome-Wide Association Studies; GWAS) from large populations of patients with late-onset Alzheimer diseases.
We investigate the pathways and interactions involved in brain ageing. We aim to find therapeutic targets and biomarkers for late-onset Alzheimer’s disease. Our scientists focus in particular on protein networks involved in the communication between nerve cells. This ambitious project integrates numerous European and national initiatives. We receive the input of four small to medium-sized enterprises allowing us to get solutions for curing and preventing common age-related diseases. The links between academia and industry is the driving force of this work program.
Our Consortium is based on the unique expertise of molecular geneticists, molecular biologists, clinicians involved in ageing diseases, computer experts and mathematicians involved in pathways modelling. A special emphasis is linked to the involvement of four small & medium enterprises (SMEs) as AgedBrainSYSBIO is expected to have potential benefit to these SMEs.
This combination of expertise is expected to give outstanding interactions to analyze and make sense of heterogeneous data sets.
Our project addresses the basis of human ageing by focusing on the identification of pathways linked to normal and pathological ageing tacking advantages of literature data of LOAD-GWAS data generated by three Partners and novel data based on patient and normal person-derived human neuron transcriptomics, drosophila and mouse models.
AgedBrainSYSBIO will obtain novel information from subsets of neurons and subregions of neurons in order to precise the location of protein-protein interactions and get a better understanding of relevant pathways through which the ageing phenotype develops in normal and/or disease conditions This topic will address the basis of human ageing by defining the interactions through which the ageing phenotype develops in normal and/or disease conditions.
Project Results:
The concept of this program is to identify subsets of pathways with two unique druggable hallmarks: the validation of interactions occurring locally in subregions of neurons and a human and/or primate accelerated evolutionary signature, using interacting approaches.
Four complementary approaches have been successfully worked out over these eighteen months:
I. Integration of multiple-level datasets for the identification of interacting protein networks including recent Late-Onset Alzheimer Disease- Genome Wide Association Studies (LOAD-GWAS) data
QURETEC is completing integration of multiple-level datasets, public datasets of expression co-variation, protein-protein interaction datasets already established or generated in this program and whole-genome epistatic interactions taking advantage of informatics capacities of Swiss Institute of BioInformatics (SIB). Novel pathways have already been identified. The most statistically significant pathways are related to axonal growth and synaptic plasticity. Potential druggable targets could be identified from this approach
The BABRAHAM group set up a quantitative model of glutamate signaling pathways, one of the most important pathways affected by Alzheimer's disease. Glutamate signaling is involved in synaptic transmission via three distinct types of receptors, AMPA, NMDA and metabotropic receptors. FYN activation and Abeta regulation was modelled in this quantitative approach (FYN activates NMDA subunits that facilitates and stabilizes NMDAR insertion).
SIB group was able to find epistatic effects of pairs of SNPs on ventricle volume, detected in Alzheimer's Disease Neuroimaging Initiative (ADNI) patients, were aggregated in a graph of epistatic interactions between genomic regions, including both genes and intergenic regions. Importantly, networks are statistically significantly enriched in genes involved in axonal growth and synaptic long term depression. These data were provided to QURETEC for integration with other interaction networks.
HYBRIGENICS identified novel protein-protein interactions (PPI) of LOAD-GWAS gene products and INSERM characterized the subcellular neuronal location of these proteins, using proximity ligation assay methods. Here again, important novel interactions were identified for LOAD-GWAS gene proteins with proteins expected to be involved either in presynaptic or in postsynaptic function.
The AgedBrainSYSBIO consortium is using meta-analysis of LOAD GWAS efforts on genome wide analysis of 54162 individuals (17008 LOAD and 37154 controls) that allowed the identification of 20 susceptibility loci - in addition to the APOE (encoding apolipoprotein E) locus, for Alzheimer's disease
These multiple-level datasets will incorporate the meta-analysis LOAD-GWAS dataset from IPL.
II. Experimental validation of interconnected networks working in subregion of a neuron (such as dendrites and dendritic spines)
Optical microscopes are subject to the diffraction barrier of light which imposes an optical resolution limit of approximately 200 nm in the imaging plane. dSTORM enables super-resolution imaging with fluorophores & probes and achieves an impressive resolution of ~ 20 nm in the imaging plan. Using proximity ligation assay (PLA) and dSTORM, INSERM group was able to locate precisely proteins coded by LOAD-GWAS genes, in particular BIN1, at the pre- and post-synaptic regions of synapses.
III. Identification of human and/or primate positive selection either in coding or in regulatory gene sequences
Genes can gain functional differences either through substitutions of specific nucleotides or by incomplete duplications/deletions. These positive selections can occur either in primates or more recently between Neanderthals and humans. TAU & INSERM are involved in the search for signals of positive Darwinian selection in genes that are known to be associated with neurodegenerative human diseases and aging. This analysis is done both at the interspecies level and within the human population.
For chromosome 21, we found GRIK1 that encodes a subunit of a glutamate kainate receptor that displays positive Darwinian selection using a statistical test to pinpoint signals of selection, the Composite of Multiple Signals (CMS) developed by Pr Sabeti’s group (Grossman et aL, Identifying recent adaptations in large-scale genomic data. Cell 2013).Another group of proteins is linked to SRGAP2 that displayed an incomplete segmental duplication around 2-3 mya, which is a time corresponding to the transition between Australophitecus to Homo. We identified novel exciting synapse-related interactors based on Yeast two-hybrid approaches.
IV. Analysis of human neurons derived from induced Pluripotent Stem Cells (iPSCs) and the development of novel drosophila and mouse transgenic models.
UDUS group characterized neuronal differentiation and neuronal phenotypes from neurons derived from induced Pluripotent Stem Cells (iPSCs). They found with INSERM that PLA techniques can be successfully applied to these human neurons. Furthermore, from lymphoblast lines of patients with rare LOAD mutations either in CR1 or in TREM2, identified by VIB group, UDUS group is establishing human neurons.
With Gene Bridges GmbH, CERBM-GIE successfully engineered mouse stem cells to locate tags for mass spectrometry and super-resolution imaging in genes involved either in synapse function or in pathophysiology of ageing and LOAD. Neurons from these ES cells are under study by INSERM group.
Potential Impact:
An expected result of the AgedBrainSYSBIO program is the release of novel datasets that will be useful to the whole European scientific community. Novel protein-protein interactions have been characterized both in fly and in human, based on Yeast two-hybrids (Y 2-H). Novel libraries for Y-2H are generated using subpopulations of neurons such as VIP and SST interneurons or subregions of human brain (entorhinal cortex, pyramidal cell layers of hippocampus and gyrus dentatus of hippocampus), in order to characterize novel protein-protein interactions in these subgroups of neurons. Furthermore, a set of novel genetically-engineered mouse transgenic lines will be released either for characterization of brain functions or for modeling precise pathways involved in normal or pathological ageing. These models are expected to be unique tools for further research in the field of synaptic function and of ageing.
The project will contribute directly to biogerontology by translating the gained knowledge to humans. As the project is dedicated to translational research: (i) from basic research to R&D in druggable targets involved in AD and (ii) from preclinical science to clinics, linicians involved in daily care of ageing patients are part of this program; This interaction is expected to translate quickly druggable targets from bench side to patient’s bed.
AgedBrainSYSBIO will contribute to improving the lives of older people. Alzheimer's disease is part of complex diseases, like hypertension or diabetes. From this complexity, it is unlikely that any one intervention will be found to delay, prevent, or cure it. So far, current approaches in treatment focus on interventions related to prevention and symptomatic treatment in order to maintain mental function, managing behavioral symptoms, and reducing or delaying the symptoms of the disease. AgedBrainSYSBIO has dedicated a work package (WP4) to Proof of Concept of Drug Discovery for Systems Medicine. This WP is led by the SME reMYND. By combining small molecules and intrabody strategies, the Consortium expects to advance in the development of therapeutic strategies for the most common aged brain disease, LOAD.
AgedBrainSYSBIO sustains the SME efforts towards research and innovation. Four European SMEs are highly implicated in the research and innovation activities of AgedBrainSYSBIO, three of them lead workpackages (WP1, WP2 & WP4). The project will increase the portfolio of these four well-established SMEs with a direct impact on economic development and employment in Europe.

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