Analysis of mouse intron 7 DNA sequence of the APP gene: comparison with the human homologue.

Mutations in the beta-amyloid precursor protein gene (APP) cause Alzheimer disease (AD) in certain families. The mature protein (APP) exists in several different isoforms resulting from alternative splicing of the primary transcript. Several lines of evidence indicate that particular isoform(s) of APP may contribute to the etiology of AD. One of the isoforms, APP695, lacks the Kunitz protease inhibitor (KPI) domain encoded by exon 7. APP695 is expressed predominantly in neurons, whereas the KPI domain containing isoforms, APP751 and APP770, are expressed ubiquitously. The ratio of APP751/APP695 mRNA tends to increase in the brain of AD patients. Furthermore, this ratio in mouse brain is much lower than that in human brain, and mice are resistant to the spontaneous development of beta-amyloidosis. In addition, transgenic mice that develop pathological changes similar to those of AD expressed more KPI-domain containing APP mRNA than transgenic mice without the changes. Previous studies imply that the controlling elements exist in the flanking sequences of the alternatively-spliced exons. Therefore, we have determined the DNA sequences of intron 7 and made a comparison between mouse and human DNA sequences of intron 7. Mouse intron 7 shares about 50% sequence identity with the human homologue, with higher sequence identity (approximately 85%) mainly in the 5' end (approximately 250 bp) of the intron. A palindromic sequence was found in both human and mouse intron 7 and showed subtle differences in their structure between the two species. Whether this sequence plays any roles in regulating alternative splicing of exon 7 remains to be determined. Human intron 7 contains a Alu element, which possesses potential retinoic acid and thyroid hormone responsive elements that might be involved in the regulation of alternative splicing. Mouse intron 7 sequence also contains a few repeat sequences which are specific to the genome of mice and rats. Homologies shared between human and mouse intron 7 sequences may contribute to the common characteristics of neuron-specific splicing of APP in both species. The unique features of the intron may account for differences between human and mouse brain in fine tuning of alternative splicing of the APP transcript, which may lead to their different susceptibilities to beta-amyloidosis.