老年性淀粉样变的发病机制新视角-横向传播的可能性

The amyloidoses are a group of protein-misfolding disorders characterized by the accumulation of amyloid fibrils formed from a variety of proteins that, under normal physiological conditions, are harmless and soluble. Currently, more than 25 amyloid diseases have been identified, including the prion diseases, Alzheimer disease, type 2 diabetes mellitus, and various systematic amyloidoses. Nonprion amyloidoses have been considered to be nontransmissible. However, investigative methods developed to study transmission of prion diseases have been applied to nonprion amyloidoses and results have suggested that in various animal models some amyloidoses can be transmitted. These are mouse apolipoprotein A-II (apoA-II) amyloidosis and inflammation-associated amyloid A (AA) amyloidosis. In mice, apoA-II, the second most abundant apoprotein in serum high-density lipoprotein (HDL), associates to form amyloid fibrils (AApoAII). It is deposited systemically, although not in the brain, in an age-associated manner. Mouse AApoAII amyloidosis has been suggested to be a disease transmitted by a prion-like process through a seeding-nucleation mechanism in SAM mouse model. Intravenous, peripheral, and oral injection of AApoAII amyloid fibrils markedly accelerated amyloid deposition in young mice. The fibrillar nuclei formed by aggregation of misfolded protein monomers act as seeds to induce and stabilize conversion of native monomeric protein. Although the transmission of disease has been revealed in mouse experiments for AApoAII, AA and cerebral amyloid ? (A?) amyloidoses, there is no epidemiological evidence that amyloidosis per se is transmissible in nature and human patients. In our previous study, Amyloid deposition has been reported to be accelerated in offspring of amyloidosis-affected mothers from consumption of milk containing AApoAII fibrils. The purpose of this study is to examine whether AApoAII amyloid deposition could be horizontally transmitted among mice through amyloid fibrils. Our unpublished data showed that the changes over time in the incidence of mouse senile amyloidosis in a mouse room. At first the incidence and degree of amyloid deposition was very low in this room. However, after we induced amyloidosis in some mice by injecting AApoAII amyloid fibrils, the degree of spontaneous amyloidosis in mice that were not injected with amyloid fibrils increased yearly. We hypothesized that amyloid fibrils retain seeding activity over a considerable length of time in the body of mice, continuous exposure to inconsequential amounts in reservoirs may lead to fibril accumulation and induction of amyloidosis. This project is to identify our hypothesis and find some new risk factors in addition to milk and feces. This project could shed new light on the causative factors involved in the high incidence of senile amyloidosis in mice.

淀粉样变疾病使体内的可溶性蛋白转化成为不溶解的淀粉样纤维，从而导致所沉积的组织及器官出现功能障碍。淀粉样纤维可以像"种子"一样，通过多种途径传播，从而诱发和促进淀粉样变的发生。我们的前期研究结果发现：老年性淀粉样变1）可以通过极微量的淀粉样纤维的静脉注射被诱导发病；2）可以通过母乳、粪便等媒介进行母子间的垂直传播；3）在进行过淀粉样变诱导实验的动物室内，小鼠的自发性淀粉样变倾向年轻化、严重化。因此，我们提出假说认为：微量的淀粉样纤维可以在生活环境中逐渐蓄积，存在于空气中，并长久保持种子的活性，借助呼吸道进行横向传播。本课题通过小鼠雾化吸入淀粉样纤维以及检测淀粉样变小鼠唾液中是否存在淀粉样纤维成分等手段，研究老年性淀粉样变的横向传播的可能性。本研究将为发现淀粉样变的传播新途径提供重要证据。

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