Expression in brain of amyloid precursor protein mutated in the alpha-secretase site causes disturbed behavior, neuronal degeneration and premature death in transgenic mice
Expression in brain of amyloid precursor protein mutated in the alpha-secretase site causes disturbed behavior, neuronal degeneration and premature death in transgenic mice
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DOI：
10.1002/j.1460-2075.1996.tb00468.x
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发表时间：
1996-03-15
期刊：
影响因子：
11.4
通讯作者：
VanLeuven, F
中科院分区：
文献类型：
--
作者：
Moechars, D;Lorent, K;VanLeuven, F
小鼠淀粉样前体蛋白(APP) β A4区域α -分泌酶位点的双重突变减少了COS细胞、极化MDCK细胞和大鼠原代神经元分泌该突变体，利用小鼠hy-1基因启动子的神经元特异性元件在小鼠大脑中表达该突变体，导致转基因小鼠逐渐过度活跃，表现为癫痫发作并过早死亡。在三种不同的转基因系中，表型的严重程度与转基因的表达水平直接相关，通过mRNA和蛋白水平来估计。此外，从每个转基因系中衍生的纯合子小鼠表现出更严重的症状，并且在生命早期出现，但观察到的症状在不同系中并没有本质上的不同：攻击性增强，对kainic酸和n -甲基- d -天冬氨酸的反应受到干扰。在大脑中，观察到的神经病理改变包括海马、皮质等区域的坏死、细胞凋亡和星形胶质细胞形成。数据表明，APP的α分泌酶加工不完整或不正确导致严重的神经毒性，并且这种作用以显性方式表达。
A double mutation in the alpha-secretase site in the beta A4 region of mouse amyloid precursor protein (APP) reduced its secretion from COS cells, polarized MDCK cells and rat primary neurons, Expression of this mutant in the brain of mice, using the neuron-specific elements of the mouse Thy-1 gene promoter, resulted in transgenic mice that became progressively hyperactive, displayed seizures and died prematurely, In three different transgenic lines the severity of the phenotype was related directly to the expression levels of the transgene, estimated by both mRNA and protein levels, In addition, homozygous mice derived from each transgenic strain showed more severe symptoms which also occurred earlier in life than in heterozygotes, The observed symptoms were, however, not essentially different in the different lines, Increased aggressiveness, disturbed responses to kainic acid and N-methyl-D-aspartate, neophobia and deficiency in exploratory behavior were demonstrated in these mice, In the brain, the observed neuropathological changes included necrosis, apoptosis and astrogliosis in the hippocampus, cortex and other areas, The data demonstrate that incomplete or incorrect alpha-secretase processing of APP results in severe neurotoxicity and that this effect is expressed in a dominant manner.