Characterisation of cytoskeletal abnormalities in mice transgenic for wild-type human tau and familial Alzheimer's disease mutants of APP and presenilin-1
Characterisation of cytoskeletal abnormalities in mice transgenic for wild-type human tau and familial Alzheimer's disease mutants of APP and presenilin-1
复制标题
DOI：
10.1016/j.nbd.2003.09.007
复制
发表时间：
2004-02-01
影响因子：
6.1
通讯作者：
Brion, JP
中科院分区：
文献类型：
--
作者：
Boutajangout, A;Authelet, M;Brion, JP
为了研究 Abeta 淀粉样蛋白沉积物在细胞骨架损伤产生中的作用，我们培育了一种转基因小鼠系，在相同的神经元中共表达野生型人 tau 异构体 (ON3R)、APP (751SL) 的突变形式和 PS1 (M146L) 的突变形式。这些小鼠在 2.5 个月大时就出现了早期脑细胞外 Abeta 沉积。仅在 tau 和 tau/PS1/APP 转基因小鼠中观察到转基因 tau 蛋白的体细胞树突神经元积聚，包括与 Abeta 沉积物相邻的神经元中。两个转基因系中体细胞树突 tau 蛋白的磷酸化状态相似。 Abeta 沉积物周围是由轴突营养不良过程组成的神经炎反应，对许多磷酸 tau 表位和人 tau 转基因蛋白具有免疫反应性。超微结构观察显示，这些营养不良的神经突中微管和神经丝网络出现紊乱，但观察到 18 个月大的动物并未出现神经原纤维缠结。这些结果表明，突变体 PS1、突变体 APP 和野生型人 tau 的过表达本身不足以驱动转基因模型中神经原纤维缠结的形成。然而，Abeta 沉积物与细胞骨架组织和邻近营养不良神经突中 tau 磷酸化的显着变化有关。 (C) 2003 Elsevier Inc. 保留所有权利。
To study the role of Abeta amyloid deposits in the generation of cytoskeletal lesions, we have generated a transgenic mouse line coexpressing in the same neurons a wild-type human tau isoform (ON3R), a mutant form of APP (751SL) and a mutant form of PS1 (M146L). These mice developed early cerebral extracellular deposits of Abeta, starting at 2.5 months. A somatodendritic neuronal accumulation of transgenic tau protein was observed in tau only and in tau/PS1/APP transgenic mice, including in neurons adjacent to Abeta deposits. The phosphorylation status of this somatodendritic tau was similar in the two transgenic lines. The Abeta deposits were surrounded by a neuritic reaction composed of axonal dystrophic processes, immunoreactive for many phosphotau epitopes and for the human tau transgenic protein. Ultrastructural observation showed in these dystrophic neurites a disorganisation of the microtubule and the neurofilament network but animals that were observed up to 18 months of age did not develop neurofibrillary tangles. These results indicate that overexpression of mutant PS1, mutant APP and of wildtype human tau were not sufficient per se to drive the formation of neurofibrillary tangles in a transgenic model. The Abeta deposits, however, were associated to marked changes in cytoskeletal organisation and in tau phosphorylation in adjacent dystrophic neurites. (C) 2003 Elsevier Inc. All rights reserved.