Objective
The proposal aims to develop transgenic mouse and rats as experimental models for Alzheimer's Disease (AD), to study the mechanism of formation and the functional consequences (cellular, tissular and behavioral) of mutations in the Amyloid Precursor Protein (APP) and the Presenilin-1 protein (PS-1). Arguments for a central role of APP in the etiology of AD are: (i) mutations in the APP gene cause severe forms of early onset familial Alzheimer's disease (EOFAD), inherited in an autosomal dominant fashion; (ii) biochemically, APP is the precursor of the ßamyloid peptide, the major constituent of amyloid plaques in the brain of AD patients and (iii) in all Down's syndrome patients (trisomy 21) supporting the hypothesis that overexpression of APP by a gene-dosage effect, or mutations force APP into abnormal metabolic pathways. Abnormal metabolism of APP could result from disturbing its intracellular sorting and/or processing.
The very recently demonstrated mutations in the Presenilin genes in different EOFAD cases, identified 2 hitherto unknown genes of unknown function, thereby adding complexity to the problem of AD but also creating a new molecular approach to understand the mechanisms involved in the etiology of AD. By in depth analysis and comparative testing of different APP and PS-1 transgenic mouse and rat strains, the mechanisms underlying neurodegeneration will be delineated.
Overexpression of mutant forms of APP and of PS-1 will be done with mini-gene constructs of cDNA using an engineered mouse Thy-1 gene promoter, directing expression of the transgene specifically to the brain in transgenic mice. Two participants are fully operational in generating transgenic mice and rats. Brains of transgenic animals will be analysed molecularly,
immunohistochemically and biochemically. For this and for behavioral testing an expert lab is participating since careful, comprehensive analysis of the different transgenic mice strains is necessary, allowing for statistical comparison. The fourth participant deals with all aspects of experimental somatic gene therapy aimed at brain, using viral vectors and transplantation of engineered cells. The fifth participant is expert in genetic analysis, i.e. APP and PS-1 genes on chromosome 21 and 14 respectively and in cell-biology of APP. The transgenic mouse and rat strains will be used to study the chronology of formation of amyloid plaques (not possible in patients); to establish the relation of ß-amyloid plaques to lesions typical in AD (neurofibrillary tangles, abnormally phosphorylated tau, neuronal degeneration); to test trophic factors (e.g. NGF), enzymes of oxidative metabolism (e.g. SOD) and pharmaca (in collaboration with industrial partners) for prevention of formation of ßA4-peptide or other neurotoxic fragments of APP or to counteract their consequences; to breed different transgenic strains to study synergistic genetic effects (genes other than APP, e.g. ApoE4; from other transgenic mouse strains under construction); derive primary cultures and stable cell-lines from the brain of transgenic mice or rats to study APP metabolism, ß-amyloid peptide production, neuronal differentiation and degeneration in-vitro.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- medical and health sciences basic medicine neurology dementia alzheimer
- medical and health sciences medical biotechnology genetic engineering gene therapy
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine transplantation
You need to log in or register to use this function
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Data not available
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
3000 LOUVAIN / LEUVEN
Belgium
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.