Modeling Alzheimer's disease in transgenic mice: effect of age and of Presenilin1 on amyloid biochemistry and pathology in APP/London mice
Modeling Alzheimer's disease in transgenic mice: effect of age and of Presenilin1 on amyloid biochemistry and pathology in APP/London mice
复制标题
DOI：
10.1016/s0531-5565(00)00149-2
复制
发表时间：
2000-09-01
影响因子：
3.9
通讯作者：
Van Leuven, F
中科院分区：
文献类型：
--
作者：
Dewachter, I;van Dorpe, J;Van Leuven, F
在过表达突变淀粉样前体蛋白[V7171]或APP/伦敦（APP/Lo）（1999 a.脑内过表达淀粉样前体蛋白不同突变体的转基因小鼠的早期表型变化。J.Biol.Chem.274，6483-6492; 1999 b.过度表达突变淀粉样蛋白前体蛋白的转基因小鼠过早死亡之前是严重的神经变性和细胞凋亡。Neuroscience 91，819-830），斑块和血管淀粉样蛋白病理学的AD相关表型是晚期的（12-15个月）。因此，这种典型的诊断性病理学在时间上与早期症状（3-9个月）分离，所述早期症状包括行为紊乱、恐新症、攻击性、谷氨酸兴奋性毒性、认知缺陷和LTP降低。因此，APP/Lo转基因小鼠是研究早期和晚期病理学（包括年龄的影响）的非常有趣的模型。在衰老的APP*Lo小鼠中，脑可溶性和特别是“不溶性”淀粉样肽显著增加，而分泌的APP α和APP β以及细胞结合的β-C-残基的标准化水平保持显著恒定，表明APP的正常α-和β-分泌酶加工。在双转基因小鼠中，即APP/Lo x PS1，临床突变型PS1[A246 E]而非野生型人PS1增加A β，并且斑块和血管淀粉样蛋白在6-9个月大时发展。PS1突变体导致A β 42产生增加，而衰老则没有。因此，淀粉样蛋白沉积物的形成不是由于A β的过度产生，而是由于衰老的APP/Lo转基因小鼠的大脑中缺乏清除和/或降解。因此，大脑淀粉样肽的清除途径是基础研究和治疗潜力的有价值的目标。尽管过度磷酸化的tau蛋白在淀粉样蛋白斑块周围的肿胀神经突中是明显的，但没有观察到神经病理学，因此AD病理学的“缠结”方面在所有当前的转基因“淀粉样蛋白”模型中仍然缺失。此外，“ApoE 4”对于迟发性AD的风险仍然是转基因小鼠建模的问题。我们已经产生过表达人ApoE 4的转基因小鼠（2000.人载脂蛋白E4在神经元中的表达导致转基因小鼠脑中蛋白mil的过度磷酸化。Am. J.病理学156（3）951-964）或人蛋白tau（1999.过度表达四重复人类tau蛋白的转基因小鼠的脑和脊髓中的突出轴突病。Am. J.病理学155. 2153-2165）在它们的神经元中。两者都发展出相似但不相同的轴突病，神经进行性变性和肌肉萎缩导致运动问题。值得注意的是，ApoE 4转基因小鼠与tau转基因小鼠一样，其特征在于运动神经元中tau蛋白的进行性过度磷酸化，这解释了运动缺陷。与APP/Lo转基因小鼠的进一步杂交正在进行中，以产生“多种”转基因小鼠品系，以研究淀粉样蛋白和tau病理学的新方面。(C)2000 Elsevier Science Inc. All rights reserved.
In transgenic mice that overexpress mutant Amyloid Precursor Protein [V7171], or APP/London (APP/Lo) (1999a. Early phenotypic changes in transgenic mice that overexpress different mutants of Amyloid Precursor Protein in brain. J. Biol. Chem. 274, 6483-6492; 1999b. Premature death in transgenic mice that overexpress mutant Amyloid precursor protein is preceded by severe neurodegeneration and apoptosis. Neuroscience 91, 819-830) the AD related phenotype of plaque and vascular amyloid pathology is late (12-15 months). This typical and diagnostic pathology is thereby dissociated in time from early symptoms (3-9 months) that include disturbed behavior, neophobia, aggression, glutamate excitotoxicity, defective cognition and decreased LTP. The APP/Lo transgenic mice are therefore a very interesting model to study early as well as Late pathology, including the effect of age. In ageing APP*Lo mice, brain soluble and especially "insoluble" amyloid peptides dramatically increased, while normalized levels of secreted APPs alpha and APPs beta, as well as cell-bound beta -C-stubs, remained remarkably constant, indicating normal alpha- and beta -secretase processing of APP. In double transgenic mice, i.e. APP/Lo x PS1, clinical mutant PS1[A246E] but not wild-type human PS1 increased A beta, and plaques and vascular amyloid developed at age 6-9 months. The PS1 mutant caused increasing A beta 42 production, while ageing did not. Amyloid deposits are thus formed, not by overproduction of A beta, but by lack of clearance and/or degradation in the brain of ageing APP/Lo transgenic mice. The clearance pathways of the cerebral amyloid peptides are therefore valuable targets for fundamental research and for therapeutic potential. Although hyper-phosphorylated protein tau was evident in swollen neurites around the amyloid plaques, neurofibrillary pathology is not observed and the "tangle" aspect of AD pathology is therefore still missing from all current transgenic "amyloid" models. Also the "ApoE4" risk for late onset AD remains a problem for modeling in transgenic mice. We have generated transgenic mice that overexpress human ApoE4 (2000. Expression of Human Apolipoprotein E4 in neurons causes hyperphosphorylation of Protein mil in the brains of transgenic mice. Am. J. Pathol. 156 (3) 951-964) or human protein tau (1999. Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am. J. Pathol. 155. 2153-2165) in their neurons. Both develop a similar although not identical axonopathy, with progressive degeneration of nerves and with muscle wasting resulting in motoric problems. Remarkably, ApoE4 transgenic mice are, like the tau transgenic mice, characterized by progressive hyper-phosphorylation of protein tau also in motor neurons which explains the motoric defects. Further crossing with the APP/Lo transgenic mice is ongoing to yield "multiple" transgenic mouse strains to study new aspects of amyloid and tau pathology. (C) 2000 Elsevier Science Inc. All rights reserved.