ANALYSIS OF AMYLOID DEPOSITION IN A TRANSGENIC MOUSE MODEL OF HOMOZYGOUS FAMILIAL AMYLOIDOTIC POLYNEUROPATHY

Amyloid fibrils derived from the Japanese, Portuguese, and Swedish typ es of familial amyloidotic polyneuropathy consist of a variant transth yretin (TTR) with a substitution of methionine for valine at position 30 (TTR Met 30). In an attempt to establish an animal model of TTR Met 30-associated homozygous familial amyloidotic polyneuropathy and to st udy the structural and functional properties of human TTR Met 30, we g enerated a mouse line carrying a null mutation at the endogenous ttr l ocus (ttr(-/-) and the human mutant ttr gene (6.0-hMet 30) as a transg ene. In these mice, human TTR Met-30-derived amyloid deposits were fir st observed in the esophagus and stomach when the mice were 11 months of age. With advancing age, amyloid deposits extended to various other tissues. Because no significant difference was detected in the onset, progression, and tissue distribution of amyloid deposition between th e ttr(-/-) and ttr(+/+) transgenic mice expressing 6.0-hMet 30, endoge nous normal mouse TTR probably does not affect the deposition of human TTR Met-30-derived amyloid in mice. TTR is a tetramer composed of fou r identical subunits that blinds thyroxine (T-4) and plasma retinol-bi nding protein. The introduction of 6.0-hMet 30 into the ttr(-/-) mice significantly increased their depressed serum levels of T-4 and retino l-binding protein, suggesting that human TTR Met 30 binds T-4 and reti nol-binding protein in vivo. The T-4-binding ability of human TTR Met 30 was confirmed by the analysis of T-4-binding proteins in the sera o f ttr(-/-) transgenic mice expressing 6.0-hMet 30. The T-4-binding stu dies also demonstrated the presence of hybrid tetramers between mouse and human TTR subunits in the ttr(+/+) transgenic mice expressing 6.0- hMet 30.