Analysis of the Pathogenesis of Familial Amyloidotic Polyneuropathy (FAP) -Application of Transgenic mice of FAP-

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We have been analyzing the physiochemical aspects of the transgenic mice with variant transthyretin gene, which is considered to be a model of Familial Amyloidotic Polyneuropathy (FAP), to know the pathogenesis of FAP. The following is the results.1. We have been keeping 100 of the pure transgenic mice with variant transthyretin gene screened by DNA analysis and immunoblotting method.2. We exsanguinated these mice every month and examined the amyloid deposition of each tissues in the autopsied transgenic mice. We found that the amyloid deposition was recognized in the small intestine, kidney, heart, thyroid and systemic small vessels of the mice from the age of 6 months. The amyloid fibrils found in these tissues were stained by anti-human TTR antibody, which was seemed to be derived from injected human mutant TTR gene. Electronmicroscopic analysis revealed that the structure of the amyloid fibrils was very similar to that in the human amyloid fibrils. However, no amyloid deposition wa … More s detected in the peripheral nerves and no pathological changes were found in these nerves.3. Analysis of purified amylold fibrils from the kidney of the transgenic mice by SDS electrophoresis revealed that major protein was detected in 15 KD band which is similar to that of TTR. According to the immunoblotting analysis, this amyloid fibril reacted with human TTR, not with anti-mice SAA. These results suggest that amyloid fibrils purified from the transgenic mice may be almost the same as those in FAP patients.4. To elucidate the role of Serum Amyloid P component (SAP), which is one of the major constituents of amyloid fibrils, we examined the starting period of amyloid deposition of the transgenic mice after inducing the peritonitis by injecting endotoxin. However, no remarkable changes were found in the amyloid deposited tissues and starting period of amyloid deposition in these mice.From these results, we concluded that mutant TTR is indispensable to show the onset of FAP and this transgenic mice is very useful to elucidate the pathogenesis of FAP. Moreover, we will evaluate the effect of the environmental factor (s), such as temperature, food and some toxins. Less