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

我们对被认为是家族性淀粉样变性多发性神经病变（Familial Amyloidotic Polyneuropathy， FAP）模型的转甲状腺素变异基因转基因小鼠进行了理化分析，以了解FAP的发病机制。结果如下：我们保留了100只经DNA分析和免疫印迹法筛选的纯转甲状腺素变异基因转基因小鼠。我们每个月给这些小鼠放血，并检查解剖后转基因小鼠各组织的淀粉样蛋白沉积。我们发现，在6个月大的小鼠的小肠、肾脏、心脏、甲状腺和全身小血管中都可以识别淀粉样蛋白沉积。在这些组织中发现的淀粉样原纤维被抗人TTR抗体染色，该抗体可能来源于注射的人TTR突变基因。电镜分析显示，淀粉样蛋白原纤维的结构与人类淀粉样蛋白原纤维非常相似。周围神经未见淀粉样蛋白沉积，未见病变。对转基因小鼠肾脏纯化的淀粉原纤维进行SDS电泳分析，发现主要蛋白位于15 KD带，与TTR相似。根据免疫印迹分析，该淀粉样蛋白原纤维与人TTR反应，而不与抗小鼠SAA反应。这些结果表明，从转基因小鼠中纯化的淀粉样蛋白原纤维可能与FAP患者的淀粉样蛋白原纤维几乎相同。为了阐明淀粉样蛋白原纤维主要成分之一的血清淀粉样蛋白P组分（SAP）的作用，我们检测了注射内毒素诱导腹膜炎后转基因小鼠淀粉样蛋白沉积的起始时间。然而，在淀粉样蛋白沉积组织和淀粉样蛋白沉积开始时间方面，没有发现明显的变化。综上所述，我们认为TTR突变体是证明FAP发病的必要条件，该转基因小鼠对阐明FAP发病机制具有重要意义。此外，我们将评估环境因素的影响，如温度、食物和一些毒素。少

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