C-terminal sequence of amyloid-resistant type F apolipoprotein A-II inhibits amyloid fibril formation of apolipoprotein A-II in mice.
C-terminal sequence of amyloid-resistant type F apolipoprotein A-II inhibits amyloid fibril formation of apolipoprotein A-II in mice.
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抗淀粉样蛋白 F 型载脂蛋白 A-II 的 C 端序列抑制小鼠载脂蛋白 A-II 淀粉样原纤维的形成。
DOI：
10.1073/pnas.1416363112
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
K.Higuchi.
中科院分区：
文献类型：
--
作者：
J.Sawashita;B.Zhang;K.Hasegawa;M.Mori;H.Naiki;F.Kametani;K.Higuchi.
在小鼠老年性淀粉样变性中，在与衰老相关的过程中，错误折叠的血清载脂蛋白（apo）A-II沉积为淀粉样纤维（AApoAII）。携带C型apoA-II（APOA 2C）蛋白的小鼠品系表现出严重的系统性淀粉样变性的高发病率。以前，我们表明，N-和C-末端序列的载脂蛋白A-II蛋白聚合成淀粉样纤维在体外是至关重要的。在这里，我们证明，携带F型载脂蛋白A-II（APOA 2F）蛋白，其中包含4个氨基酸取代的APOA 2C的淀粉样蛋白生成区域的同类小鼠品系，是绝对抗淀粉样变性，即使在诱导淀粉样变性AApoAII注射。体外原纤维形成试验表明，N-和C-末端APOA 2F肽没有形成淀粉样原纤维。此外，C-末端APOA 2F肽是聚合过程中淀粉样纤维成核和延伸的强抑制剂。重要的是，在诱导淀粉样变性后，我们通过C-末端APOA 2F肽治疗，成功地抑制了老年淀粉样变性易感小鼠的淀粉样蛋白沉积。我们认为C-末端APOA 2F肽可能通过阻断核（种子）的活性末端来抑制淀粉样纤维的进一步延伸。我们提出了一个以前未确定的模型系统，用于研究体内和体外对淀粉样变性的抑制机制，并相信该系统将有助于开发新的治疗方法。
In murine senile amyloidosis, misfolded serum apolipoprotein (apo) A-II deposits as amyloid fibrils (AApoAII) in a process associated with aging. Mouse strains carrying type C apoA-II (APOA2C) protein exhibit a high incidence of severe systemic amyloidosis. Previously, we showed that N- and C-terminal sequences of apoA-II protein are critical for polymerization into amyloid fibrils in vitro. Here, we demonstrate that congenic mouse strains carrying type F apoA-II (APOA2F) protein, which contains four amino acid substitutions in the amyloidogenic regions of APOA2C, were absolutely resistant to amyloidosis, even after induction of amyloidosis by injection of AApoAII. In vitro fibril formation tests showed that N- and C-terminal APOA2F peptides did not polymerize into amyloid fibrils. Moreover, a C-terminal APOA2F peptide was a strong inhibitor of nucleation and extension of amyloid fibrils during polymerization. Importantly, after the induction of amyloidosis, we succeeded in suppressing amyloid deposition in senile amyloidosis-susceptible mice by treatment with the C-terminal APOA2F peptide. We suggest that the C-terminal APOA2F peptide might inhibit further extension of amyloid fibrils by blocking the active ends of nuclei (seeds). We present a previously unidentified model system for investigating inhibitory mechanisms against amyloidosis in vivo and in vitro and believe that this system will be useful for the development of novel therapies.