COMPARISON OF AMYLOID DEPOSITION IN 2 LINES OF TRANSGENIC MOUSE THAT MODEL FAMILIAL AMYLOIDOTIC POLYNEUROPATHY, TYPE-I

We previously produced a transgenic mouse line designated MT-hMet30 by introducing the human mutant transthyretin (TTR) gene carrying the mo use metallothionein promoter, and showed that the presence of human va riant TTR is sufficient for amyloid deposition in various tissues of t hese transgenic mice. However, the expression pattern of human mutant transthyretin gene in the mouse was different from that in man. To ana lyse pathologic processes, it is essential to establish a transgenic m ouse line in which the developmental and tissue-specific expression of the human mutant TTR gene is the same as in man. Thus, we produced tw o additional transgenic mouse lines carrying the human mutant TTR gene containing either 0.6 kb (0.6-hMet30) or 6.0 kb (6.0-hMet30) of the u pstream region. The expression levels of 6.0-hMet30 gene in the liver and serum were the same as in man and about 10 times higher than those of 0.6-hMet30 gene. Ln both lines amyloid deposition was observed in similar tissues to human patients except for the peripheral and autono mic nervous tissues. The amyloid deposition started earlier and was mo re extensive in 6.0-hMet30 than 0.6-hMet30 mice, suggesting that the s erum levels of human mutant TTR are correlated with the occurrence and degree of amyloid deposition, to some extent. Neither amyloid deposit ion nor degenerative changes were observed in the peripheral and auton omic nervous systems despite the transgene expression in the choroid p lexus of the 6.0-hMet30 mice. In the 6.0-hMet30 mice, amyloid depositi on started at 9 months of age, although the serum level of human mutan t TTR reached the adult level at 1 month. These results suggest that i ntrinsic environmental factors other than the mutant gene are involved in the late-onset deposition of amyloid fibrils. Transgenic mice desc ribed here should be useful for analysing such factors.