Early formation of mature amyloid-β protein deposits in a mutant APP transgenic model depends on levels of Aβ1-42
Early formation of mature amyloid-β protein deposits in a mutant APP transgenic model depends on levels of Aβ1-42
复制标题
DOI：
10.1002/jnr.1247
复制
发表时间：
2001-11-15
影响因子：
4.2
通讯作者：
Masliaha, E
中科院分区：
文献类型：
--
作者：
Rockenstein, E;Mallory, M;Masliaha, E
本研究的主要目的是开发一种替代的单转基因（tg）hAPP模型，其中淀粉样蛋白沉积将在较早的年龄发生。为此，我们产生了表达hAPP 751 cDNA的tg小鼠系，该hAPP 751 cDNA含有在鼠（m）Thy-1基因（mThyl-hAPP 751）的调控控制下的伦敦（V7171）和瑞典（K670 M/N671 L）突变。在最高（线41）和中间（线16和11）表达者的脑中，在新皮层、海马CA 1和嗅球的第4-5层中的神经元中发现高水平的hAPP表达。早在3-4个月大时，41号系小鼠的额叶皮质就出现了成熟的斑块，而在5-7个月大时，斑块形成扩展到海马体、丘脑和嗅觉区域。超微结构和双免疫标记分析证实，大多数斑块是成熟的，并含有营养不良的神经突起与APP，突触素，神经丝和tau蛋白的抗体免疫反应。此外，突触素免疫反应性终末数量的减少在第41行小鼠的额叶皮层中最为突出。11号系小鼠在11月龄时出现弥漫性淀粉样蛋白沉积，而16号系小鼠未显示淀粉样蛋白沉积的证据。通过ELISA对A β的分析显示，在未显示任何淀粉样蛋白沉积的小鼠中A β（1-40）的水平较高（第16行），而在来自显示斑块形成的品系的tg动物中A β（1-42）是主要种类（第41和11行）。总之，这项研究表明，早发性斑块的形成取决于A β（1-42）的水平。神经科学杂志Res. 66：573-582，2001. (C)2001 Wiley-Liss，Inc.
The main objective of the present study was to develop an alternative singly-transgenic (tg) hAPP model where amyloid deposition will occur at an earlier age. For this purpose, we generated lines of tg mice expressing hAPP751 cDNA containing the London (V7171) and Swedish (K670M/N671L) mutations under the regulatory control of the murine (m)Thy-1 gene (mThyl-hAPP751). In the brains of the highest (line 41) and intermediate (lines 16 and 11) expressers, high levels of hAPP expression were found in neurons in layers 4-5 of the neocortex, hippocampal CA1 and olfactory bulb. As early as 3-4 months of age, line 41 mice developed mature plaques in the frontal cortex, whereas at 5-7 months plaque formation extended to the hippocampus, thalamus and olfactory region. Ultrastructural and double-immunolabeling analysis confirmed that most plaques were mature and contained dystrophic neurites immunoreactive with antibodies against APP, synaptophysin, neurofilament and tau. In addition, a decrease in the number of synaptophysin-immunoreactive terminals was most prominent in the frontal cortex of mice from line 41. Mice from line 11 developed diffuse amyloid deposits at 11 months of age, whereas mice from line 16 did not show evidence of amyloid deposition. Analysis of Ap by ELISA showed that levels of A beta (1-40) were higher in mice that did not show any amyloid deposits (line 16), whereas A beta (1-42) was the predominant species in tg animals from the lines showing plaque formation (lines 41 and 11). Taken together this study indicates that early onset plaque formation depends on levels of A beta (1-42). J. Neurosci. Res. 66:573-582, 2001. (C) 2001 Wiley-Liss, Inc.