Objective
To create transgenic mouse strains in which specified aspects of the etiology of Alzheimer's Disease are modelled by overexpression of normal and mutant forms of the Amyloid Precursor Protein.
Transgenic mouse strains were created with specific and exclusive overexpression of a designed APP alpha-secretase mutant in brain (t/APP/RK). This resulted in a typical, robust and reproducible phenotype reacpitulating certain aspects of AD In addition to aggression, and changes in behavior (neophobia, posture freezing, reduced thigmotaxis), occasional seizures (progressing in severity with age) could be related to altered responses to glutamatergic agonists (increased sensitivity to kainic acid and largely refractory to NMDA). Death occurrs prematurely (from 3 months of age) without signs of deteriorating health, no weight loss, no internal malformations nor bleedings. Post-mortem analysis of brain demonstrated severe neurodegeneration and apoptosis in the hippocampus, especially dentate gyrus and in cerebral cortex as well as astrogliosis (GFAP staining). The severity pregresses with age and is directly related to APP/RK expression levels in brain (in different strains and in homozygotes). Formation of betaA4-peptide and amyloid plaques were never observed, directly addressing the classic problem in AD: plaques and neurodegeneration can be cause, correlation or consequence. This model complies with a report on tg mice with intra-neuronal expression of betaA4-peptide resulting in almost identical phenotype as our APP/RK tg mice (LaFerla et al, Nature Genetics 1995 9:21-29). In addition, massive amyloid plaques in brain of tg mice do not notably result in neurodegeneration (Games et al, Nature 1995 373:523-527). Finally, APP deficiency is phenotypically almost silent (Zheng et al, Cell 1995 81:525-531) demonstrating that APP or its metabolic derivatives are neurotoxic by mechanisms that can be traced in our APP/RK tg model. This will be further analyzed by introducing 4 clinical APP mutants for expression in cells and in tg mice. The Presenilin 1 gene (EOFAD gene, chromosome 14) was cloned from 2 Belgian families (most severe AD phenotype known) and the mutations identified: I143-T in family AD/A, G384-A in family AD/B. Expression studies and construct synthesis are initiated. CNS directed gene therapy was pursued by injection of viral vectors carrying cDNA or genomic sequences; transplantation of neurons that were genetically altered by viral infection or by transfection (transplanted `transgenic neurons' express human APP in rodent brain for almost a year); transplantation of brain tissue from mice with trisomy 16 mice (equivalent to human trisomy 21 in Down's syndrome). These studies have resulted in 4 joint publications.
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
- medical and health sciences clinical medicine transplantation
- natural sciences biological sciences genetics chromosomes
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Coordinator
3000 Leuven
Belgium
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