Objective
Alzheimer's disease (AD) is characterised by plaques and tangles in the brain.
The plaques are areas of disorganized neurones with B-amyloid deposits at the centre as the major protein component.
B-amyloid deposition in the brain is a diagnostic hallmark of AD, and has most probably a causative role in the disease.
B-amyloid is a highly aggregating 39-42 amino acid peptide that is a break down product of the amyloid precursor protein (APP).
Disease causing mutations in the APP gene have been found during the last two years in some earlyonset AD families.
Two different APP codons are involved in mutations causing AD, codon 717 and codon 670/671, the latter in a Swedish AD family.
Although the mutations are rare causes of the disease, they point to a general mechanism of aetiology and pathogenesis.
The objective of this concerted action between Sweden, Germany and Italy is to create an animal model for AD by the establishment of transgenic rats expressing the human gene with the APP 670/671 mutation.
Furthermore, the transgenic AD rats will be cross-bred with transgenic hypertensive rats, in order to mimic risk factors for dementia. The major impediment to understanding the pathogenesis of AD, and to develope a treatment, is the lack of an animal model.
Attempts to create a transgenic mouse model for AD have so far met with little success.
Mice may simply not live long enough for AD pathology to develope. It therefore becomes important to try another species than mouse for the transgenic approach to AD.
It has been proposed that the effects of the APP mutations are to cause a greater proportion of APP to be metabolised to B-amyloid.
Cell cultures transfected with the APP 670/671 mutation give rise to high levels of B-amyloid production.
We will use a DNA construct harbouring the Swedish APP 670/671 mutation. The ideal result would be a rat, where expression of human APP with the codon 670/671 mutation gives rise to AD pathology whereas a rat with the normal human APP gene gives no AD pathology.
A transgenic rat expressing AD pathology will be of great importance in analysing the pathogenesis and developing treatments for the disease.
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Topic(s)
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CSC - Cost-sharing contractsCoordinator
13092 Berlin
Germany
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Participants (2)
141 86 Huddinge
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50134 Firenze
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