Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain
Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain
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DOI：
10.1074/jbc.274.10.6483
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发表时间：
1999-03-05
影响因子：
4.8
通讯作者：
Van Leuven, F
中科院分区：
文献类型：
--
作者：
Moechars, D;Dewachter, I;Van Leuven, F
过表达不同形式的淀粉样前体蛋白（APP），即野生型或临床突变体的转基因小鼠，表现出基本上可比较的早期表型的行为，差异性神经元能反应，在维持长时程增强的缺陷，和过早死亡。在不同APP转基因品系的F1代杂种中，早在3个月大时，认知障碍就与非转基因同窝仔有显著差异。对脑中分泌的和膜结合的APP、C-末端"残端"以及A β（40）和A β（42）肽的生化分析表明，没有单一的中间体可以负责表型功能障碍的复杂性。正如预期的，A β（42）水平在APP/伦敦转基因小鼠中最显著，并且与该品系的老年小鼠中淀粉样蛋白斑块的形成直接相关。斑块与过度磷酸化tau的免疫反应性相关，最终发出某种形式的tau病理信号。总之，研究的不同APP转基因小鼠品系在生命早期显示出认知缺陷和表型特征，这些特征与淀粉样斑块的形成及时分离，并且将成为阿尔茨海默病早期和晚期神经病理学和临床方面的良好模型。
Transgenic mice overexpressing different forms of amyloid precursor protein (APP), i.e. wild type or clinical mutants, displayed an essentially comparable early phenotype in terms of behavior, differential glutamatergic responses, deficits in maintenance of long term potentiation, and premature death. The cognitive impairment, demonstrated in F1 hybrids of the different APP transgenic lines, was significantly different from nontransgenic littermates as early as 3 months of age. Biochemical analysis of secreted and membrane-bound APP, C-terminal "stubs," and A beta(40) and A beta(42) peptides in brain indicated that no single intermediate can be responsible for the complex of phenotypic dysfunctions. As expected, the A beta(42) levels were most prominent in APP/London transgenic mice and correlated directly with the formation of amyloid plaques in older mice of this line, Plaques were associated with immunoreactivity for hyperphosphorylated tau, eventually signaling some form of tau pathology. In conclusion, the different APP transgenic mouse lines studied display cognitive deficits and phenotypic traits early in life that dissociated in time from the formation of amyloid plaques and will be good models for both early and late neuropathological and clinical aspects of Alzheimer's disease.