Analysis of the mechanism of misfolding to amyloid protein using mouse amyloidosis

我们研究了小鼠AApoAII淀粉样变，以阐明各种淀粉样变的共同机制。我们得到了以下结果：1)我们发现淀粉样蛋白携带的老年小鼠通过食用老年小鼠的粪便将淀粉样蛋白病传染给年轻小鼠。2)注射淀粉样蛋白原纤维诱导正常小鼠和抗淀粉样变小鼠发生淀粉样变。3)原位杂交分析显示，apoA-II的肝外合成可能促进了局部组织淀粉样蛋白纤维的形成。4)研究了不同淀粉样原纤维对AApoAII淀粉样变性的诱导作用。所有的淀粉样蛋白原纤维静脉注射到小鼠诱导淀粉样变性。注射的淀粉样原纤维沉淀到淀粉样变性组织（肺、舌、胃等），并可能作为淀粉样原纤维形成的模板（种子）。5) R1大鼠淀粉样变加速。注射AApoAII诱导小鼠发生严重淀粉样变性的P1-Apoa2c小鼠。6)我们发现在一个动物中心饲养的抗淀粉样蛋白A型apoA-II型C57BL小鼠出现了严重的淀粉样变，而在R1中没有淀粉样蛋白沉积。SPf条件下培养淀粉样变性C型apoA-II P1-Apoa2c小鼠。我们尝试开发淀粉样变的治疗方法。注射具有抗淀粉样蛋白apoA-II cDNA的腺病毒，含红花油作为脂质的食物在体内抑制淀粉样变性，抗氧化剂（利福平和NDGA）在体内抑制纤维形成。这些结果表明，具有淀粉样原纤维样结构的外源性物质的入侵可能作为种子，引发内源性淀粉样蛋白的构象变化，从而聚合成淀粉样原纤维。小鼠淀粉样变是研究疾病病理中遗传与环境因素关系的良好模型。

We studied mouse AApoAII amyloidosis to elucidate the common mechanism of valious amyloidosis. We obtained the following results,1)We found transmission of amyloidosis from old amyloid laden mice to young mice by eating feces of old mice.2)Injection of amyloid fibrils induced amyloidosis in normal and amyloidosis resistant mice.3)In situ hybridization analysis revealed that extra-hepatic synthesis of apoA-II may contribute amyloid fibril formation in the local tissues.4)We studied the induction of AApoAII amyloidosis by various kind of amyloid fibrils. All amyloid fibrils injected intravenously into mice induced amyloidosis. Injected amyloid fibrils settle to amyloidogenic tissues(the lungs, tongue, stomach ets.)and might act as template(seed)for amyloid fibril formation.5)Acceleration of amyloidosis was observed in R1.P1-Apoa2c mice born from the mother mice in which severe amyloidosis was induced by AApoAII injection.6)We found severe amyloidosis in C57BL mice with amyloid-resistant type A apoA-II reared in one animal center and no amyloid deposition in R1.P1-Apoa2c mice with amyloidogenic type C apoA-II reared in SPf condition.7)We tried to develop the therapeutic methods for amyloidosis. Injection of adeno-virus with amyloid resistant apoA-II cDNA, food containing safflower oil as a lipid inhibited amyloidosis in vivo and anti-oxidant(rifanpicine and NDGA)inhibited fibril formation in vivo.These results suggested that invasion of exogenous substances with amyloid-fibril-like structures may act as seeds and trigger the conformational change of endogenous amyloid protein to polymerize into amyloid fibril.Mouse amyloidosis is a good model for study of the relationship between genetic and environmental factors in pathology of diseases.