Community Research and Development Information Service - CORDIS

FP7

AGEDBRAINSYSBIO Report Summary

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

Periodic Report Summary 2 - AGEDBRAINSYSBIO (SYSTEMS BIOLOGY OF PATHWAYS INVOLVING BRAIN AGEING)

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:
Five complementary approaches have been successfully worked out over these three years:
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
Integration of various data types by QUERETEC in the consistent manner gives an opportunity to study Alzheimer’s disease through the network of complex interactions aggregated as a single data source.
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.
New Run of epistatic analysis has been conducted by SIB using Whole Genome Sequencing data (WGS) using complete sequence data provided by the ADNI consortium for 819 patients were imported to the SIB computing system, using a dedicated machine for the transfer of a total size of 85 tera bytes from the LONI Laboratory of Neuro Imaging, at the University of Southern California, to Switzerland. Single-locus association and Epistasis between candidate genes have been demonstrated between genetic variants and AD-related longitudinal phenotype, the ventricular enlargement rate (VER).
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, demonstrating networks involved either in pre and 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 dataset incorporate the meta-analysis LOAD-GWAS dataset from IPL.
II. BIN1 BAC transgenic mice display typical early neurocognitive pathologic features of LOAD
BAC BIN1 mice have been established by the consortium. They have a specific defect in synaptic plasticity in a pathway (entorhinal cortex -> dentate gyrus) known to be the starting point of LOAD in humans. Furthermore, these mice display impacted novel object recognition. Molecular mechanisms involved changes in postsynaptic proteins of synapses between entorhinal cortex and dentate gyrus.
This mouse model can be instrumental to test novel therapeutic approaches of LOAD.
III. Identification of human and/or primate positive selection either in coding or in regulatory gene sequences
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. This analysis focused on chromosome 21, as a model system.
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) obtained from lymphoblast lines of patients with rare LOAD mutations (CR1 or TREM2) from VIB group.
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.
V. Analysis of rare variants from LOAD-GWAS patients
VIB group identified loss-of-function mutations in a LOAD-GWAS gene, ABCA7, in a resequencing study. Cuyvers et al. Lancet Neurology, 14(8):814-22, 2015 (I.F. 24.075).

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 20 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, clinicians 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. We are starting strategies using intrabodies against TAU and FYN using stereotaxic injections in diverse Alzheimer’s Disease mouse models, including models generated by the AgedBrainSYSBIO consortium. Interestingly, two recent studies published in 2015 demonstrated that antibodies against cis P-tau and inhibitors of FYN impacts pathophysiological steps of Alzheimer in mouse models (Kondo et al., Nature 2015; Kaufman et al., Ann Neurol. 2015).
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

List of Websites:
www.agedbrainsysbio.eu

Related information

Reported by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM)
France
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