Abstract
Alzheimer’s disease can be modelled by different transgenic mouse strains. To gain deeper insight into disease model mechanisms, the previously described Tg4–42 mouse was analysed for transgene integration. On RNA/DNA level the transgene integration resulted in more than 20 copy numbers and further caused a deletion of exon 2 of the retinoic acid receptor beta. These findings were also confirmed on protein level with highly decreased retinoic acid receptor beta protein levels in homozygous Tg4–42 mice and may have an impact on the previously described phenotype of homozygous Tg4–42 mice to be solely dependent on amyloid-ß 4–42 expression. Since hemizygous mice show no changes in RARB protein levels it can be concluded that the previously described phenotype of these mice should not be affected by the retinoic acid receptor beta gene knockout. In order to fully understand the results of transgenesis, it is extremely advisable to determine the genome integration site and the basic structure of the inserted transgenes. This can be carried out for instance by next-generation sequencing techniques. Our results thus suggest that a detailed characterization of new disease models using the latest genomics technologies prior to functional studies could be a valuable tool to avoid an unexpected genetic influence on the animals’ phenotype that is not only based on the inserted transgene. This would also significantly improve the selection of mouse models that are best suited for therapeutic development and basic research.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and mainly characterized by progressive neurodegeneration as well as extracellular accumulation of amyloid-ß protein (Aß) that is surrounded by dystrophic neurites and neurofibrillary tangles[1]
Targeted Locus Amplification of the Tg4–42 + /+ mouse model showed that the Aβ4–42 transgene is inserted in more than 20 copies of head to tail orientation at position 17,431,476– 17,651,381 on chromosome 14
Exon 2 of the retinoic acid receptor beta (RARB) gene was deleted in Tg4–42 mice (Fig. 1a)
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and mainly characterized by progressive neurodegeneration as well as extracellular accumulation of amyloid-ß protein (Aß) that is surrounded by dystrophic neurites and neurofibrillary tangles[1]. Homozygous Tg4–42 mice exhibit no significant target quadrant preferences in the Morris water maze behaviour test, which indicates severe impairments in spatial memory. Homo- and hemizygous Tg4–42 mice that were allowed to exercise in enriched housing conditions revealed improved performance on the balance beam, rotarod and rescued performance in the Morris water maze test. This increased physical activity caused decreased neuron loss which resulted in a higher number of CA1 pyramidal cells[7]. Decreased expression and reduced protein levels of the retinoic acid receptor beta in brain tissue of homozygous Tg4–42 mice was found, questioning the cause of the previously described phenotype in homozygous Tg4–42 mice to be solely dependent on Aß4–42 expression
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