Ge Fengxia, Yao Junjie, Fu Xiaoying, Guo Zhanjun, Yan Jingmin, Zhang Beiru, Zhang Huanyu, Tomozawa Hiroshi, Miyazaki Junichi, Sawashita Jinko, Mori Masayuki, Higuchi Keiichi
Department of Aging Biology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
Lab Invest. 2007 Jul;87(7):633-43. doi: 10.1038/labinvest.3700559. Epub 2007 Apr 30.
In mice, apolipoprotein A-II (apoA-II) self-associates to form amyloid fibrils (AApoAII) in an age-associated manner. We postulated that the two most important factors in apoA-II amyloidosis are the Apoa2(c) allele, which codes for the amyloidogenic protein APOA2C (Gln5, Ala38) and transmission of amyloid fibrils. To characterize further the contribution of the Apoa2(c) allele to amyloidogenesis and improve detection of amyloidogenic materials, we established transgenic mice that overexpress APOA2C protein under the cytomegalovirus (CMV) immediate early gene (CMV-IE) enhancer/chicken beta promoter. Compared to transgene negative (Tg(-/-)) mice that express apoA-II protein mainly in the liver, mice homozygous (Tg(+/+)) and heterozygous (Tg(+/-)) for the transgene express a high level of apoA-II protein in many tissues. They also have higher plasma concentrations of apoA-II, higher ratios of ApoA-II/apolipoprotein A-I (ApoA-I) and higher concentrations of high-density lipoprotein (HDL) cholesterol. Following injection of AApoAII fibrils into Tg(+/+) mice, amyloid deposition was observed in the testis, liver, kidney, heart, lungs, spleen, tongue, stomach and intestine but not in the brain. In Tg(+/+) mice, but not in Tg(-/-) mice, amyloid deposition was induced by injection of less than 10(-8) mug AApoAII fibrils. Furthermore, deposition in Tg(+/+) mice occurred more rapidly and to a greater extent than in Tg(-/-) mice. These studies indicate that increased levels of APOA2C protein lead to earlier and greater amyloid deposition and enhanced sensitivity to the transmission of amyloid fibrils in transgenic mice. This transgenic mouse model should prove valuable for studies of amyloidosis.
在小鼠中，载脂蛋白A-II（apoA-II）会以与年龄相关的方式自我缔合形成淀粉样纤维（AApoAII）。我们推测，apoA-II淀粉样变性中两个最重要的因素是编码淀粉样蛋白APOA2C（Gln5，Ala38）的Apoa2(c)等位基因以及淀粉样纤维的传播。为了进一步表征Apoa2(c)等位基因对淀粉样变性的贡献并改进对淀粉样蛋白生成物质的检测，我们构建了在巨细胞病毒（CMV）立即早期基因（CMV-IE）增强子/鸡β启动子控制下过表达APOA2C蛋白的转基因小鼠。与主要在肝脏中表达apoA-II蛋白的转基因阴性（Tg(-/-)）小鼠相比，转基因纯合子（Tg(+/+)）和杂合子（Tg(+/-)）小鼠在许多组织中都表达高水平的apoA-II蛋白。它们的血浆apoA-II浓度也更高，ApoA-II/载脂蛋白A-I（ApoA-I）的比例更高，高密度脂蛋白（HDL）胆固醇浓度也更高。将AApoAII纤维注射到Tg(+/+)小鼠体内后，在睾丸、肝脏、肾脏、心脏、肺、脾脏、舌头、胃和肠道中观察到淀粉样沉积，但在大脑中未观察到。在Tg(+/+)小鼠中，注射少于10^(-8)微克的AApoAII纤维即可诱导淀粉样沉积，而Tg(-/-)小鼠则不会。此外，Tg(+/+)小鼠中的沉积比Tg(-/-)小鼠发生得更快且程度更大。这些研究表明，APOA2C蛋白水平的升高会导致转基因小鼠中更早、更大量的淀粉样沉积，并增强对淀粉样纤维传播的敏感性。这种转基因小鼠模型对于淀粉样变性的研究应该具有重要价值。
