Studies of the Pathogenesis of Amyloidosis : Verification of the Hypothesis 'Transmission of Abnormal Proteins Structure' Using Mouse Senile Amyloidosis.

淀粉样变性是一组以淀粉样纤维组织沉积为特征的疾病。一次静脉注射极少量的天然小鼠老年性淀粉样蛋白纤维(AApoAII)可诱导携带致淀粉样蛋白A-II基因(APOA2^c)的幼鼠体内严重的系统性淀粉样蛋白沉积。ApoAII注射后，在自发性老年性淀粉样变性小鼠中观察到淀粉样蛋白沉积迅速，并加速推进。然而，将具有相同一级结构但没有纤维构象的变性载脂蛋白A II、天然载脂蛋白A-II和变性载脂蛋白A-II单体注射到高密度脂蛋白中，并没有引起淀粉样变性。这些发现表明，体外发现的成核依赖的聚合也在体内发生，并且注射的淀粉样纤维在体内作为种子所需的纤维构象。我们将从老年R1.P1-APOA2^c小鼠的肝脏中分离的ApoAII淀粉样纤维注射到胃…中更多的幼鼠连续五天使用喂食针。2个月后，所有小鼠的小肠固有层都有ApoAII沉积。在喂养后3个月和4个月，淀粉样蛋白沉积扩展到舌、胃、心脏和肝脏。ApoAII悬浮在饮用水中也会引起淀粉样变性。在同一个笼子里饲养三个月的年轻小鼠和患有严重淀粉样变性的老年小鼠都被诱导了淀粉样蛋白沉积。老年小鼠粪便中ApoAII的检测表明，ApoAII是通过进食粪便传播的。纤维构象依赖性纤化被认为是体内发生的各种淀粉样变性发病机制的通用模型。进一步，我们证实了ApoAII淀粉样变性的遗传性，并提出了淀粉样变性独特的发病机制--淀粉样蛋白纤维构象的口头传递，即外源淀粉样纤维作为种子入侵，改变内源淀粉样蛋白的构象聚合成淀粉样纤维。较少

Amyloidosis refers to a group of diseases characterized by tissue deposition of amyloid fibrils. A single intravenous injection of a very small amount of the native mouse senile amyloid fibrils (AApoAII) induced severe systemic amyloid deposition in young mice having the amyloidogenic apoA-II gene (Apoa2^c). After AApoAII injection, amyloid deposition occurred rapidly, and advanced in an accelerated manner observed in spontaneous senile amyloidosis in mice. However, the injection of denatured AApoAII, native apoA-II in high density lipoprotein (HDL) and denatured apoA-II monomer which have the same primary structure but without a fibril conformation did not induce amyloidosis. These findings suggested that the nucleation-dependent polymerization found in vitro also occurs in vivo, and that the fibril conformation is required for the injected amyloid fibrils to act as seeds in viva.We injected AApoAII amyloid fibrils isolated from the liver of an old R1.P1-Apoa2^c mouse into the stomach … More of young mice using feeding needles for five consecutive days. After 2 months, all mice had AApoAII deposits in the lamina propria of the small intestine. Amyloid deposition extended to the tongue, stomach, heart and liver at 3 and 4 months after feeding. AApoAII suspended in drinking water also induced amyloidosis. Amyloid deposition was induced in young mice reared in the same cage for three months with old mice that had severe amyloidosis. Detection of AApoAII in feces of old mice suggested the transmission by eating of feces.Fibril conformation-dependent fibrillization is proposed as a general model of the pathogenesis of various kinds of amyloidosis occurring in viva. Further, we substantiated the transmissibility of AApoAII amyloidosis and presented the unique pathogenesis of amyloidosis "oral transmission of amyloid fibril conformation", that is, invasion of exogenous amyloid fibrils acts as seeds and changes the conformation of endogenous amyloid protein to polymerize into amyloid fibrils. Less