Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695
Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695
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DOI：
10.1074/jbc.m100710200
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发表时间：
2001-06-15
影响因子：
4.8
通讯作者：
Westaway, D
中科院分区：
文献类型：
--
作者：
Chishti, MA;Yang, DS;Westaway, D
我们已经建立了早发性转基因（Tg）模型，利用家族性阿尔茨海默病突变对淀粉样蛋白P肽（Ap）生物合成的协同作用。TgCRND 8小鼠在PrP基因启动子的控制下编码淀粉样前体蛋白695的双突变形式（KM 670/671 NL + V717 F）。硫磺素S阳性AP淀粉样蛋白沉积物在3个月时出现，致密核心斑块和神经炎病理从5个月大开始明显。TgCRND 8小鼠在6月龄时表现出每克脑3，200 - 4，600 pmol的A β 42，A β 42超过A β 40。致病性A β 42形式A β肽的高水平产生与TgCRND 8小鼠在参考记忆版本的Morris水迷宫中的获得和学习逆转中的早期损伤相关，存在于3个月大时。值得注意的是，幼龄小鼠的学习障碍通过针对A β 42的免疫而被抵消（Janus，C.，Pearson，J.，McLaurin，J.，马修斯，P. M.，江，Y.，施密特，S. D、Chishti，M.一、Horne，P.，Heslin，D.，弗伦奇，J.，芒特，H。T. J.，尼克松，R.一、Mercken，M.，Bergeron，C.，弗雷泽，体育，St. George-Hyslop，P.和Westaway，D.（2000）Nature 408，979-982）。早老素1转基因（包括家族性阿尔茨海默病突变）的表达增强了TgCRND 8小鼠中的淀粉样蛋白沉积;对于还表达M146 L + L286 V早老素1转基因的小鼠，淀粉样蛋白沉积在1个月龄时明显。这里描述的Tg小鼠表明在短时间内研究阿尔茨海默病发病机制、预防和治疗方面的潜力。
We have created early-onset transgenic (Tg) models by exploiting the synergistic effects of familial Alzheimer's disease mutations on amyloid P-peptide (Ap) biogenesis. TgCRND8 mice encode a double mutant form of amyloid precursor protein 695 (KM670/671NL+V717F) under the control of the PrP gene promoter. Thioflavine S-positive AP amyloid deposits are present at 3 months, with dense-cored plaques and neuritic pathology evident from 5 months of age. TgCRND8 mice exhibit 3,200-4,600 pmol of A beta 42 per g brain at age 6 months, with an excess of A beta 42 over A beta 40. High level production of the pathogenic A beta 42 form of A beta peptide was associated with an early impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of age. Notably, learning impairment in young mice was offset by immunization against A beta 42 (Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T. J., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., St. George-Hyslop, P., and Westaway, D. (2000) Nature 408, 979-982). Amyloid deposition in TgCRND8 mice was enhanced by the expression of presenilin 1 transgenes including familial Alzheimer's disease mutations; for mice also expressing a M146L+L286V presenilin 1 transgene, amyloid deposits were apparent by 1 month of age. The Tg mice described here suggest a potential to investigate aspects of Alzheimer's disease pathogenesis, prophylaxis, and therapy within short time frames.