German Dwight C, Eisch Amelia J
Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, TX 75390-9070, USA.
Rev Neurosci. 2004;15(5):353-69. doi: 10.1515/revneuro.2004.15.5.353.
Mice overexpressing mutant Alzheimer's disease (AD)-related proteins exhibit many of the neuropathological and behavioral features of the human disease. Transgenic animals have been created that express mutations in the amyloid precursor protein (APP), presenilin (PS)1, and PS2, and also animals expressing more than one of these mutations. For example, in APP mouse models, there are age-related accumulations of amyloid-beta (Abeta)-containing neuritic plaques in the hippocampus and cerebral cortex, activation of astrocytes and microglial cells in regions containing plaques, and degeneration of cholinergic nerve terminals in brain regions that eventually become plaque containing. Missing in the APP and PS mouse models are neurofibrillary tangles and robust neuronal loss in cerebral cortical and subcortical regions such as the basal forebrain cholinergic and locus coeruleus noradrenergic nuclei. Neurofibrillary tangles can be produced in mice expressing mutant tau protein, and the tangle formation is further enhanced in animals that also express mutant APP. Studies in APP mouse models indicate that, like AD, there are abnormalities in adult hippocampal neurogenesis. The animal models of AD have been used to develop and test treatments that reduce brain levels of the Abeta42 protein, neuritic plaque load and glial activation, and some have been found to restore learning and memory function. If such treatments can be shown to stop the neurodegenerative process and restore hippocampal neurogenesis, damaged brain circuits may be replaceable in patients with AD.
过度表达与阿尔茨海默病（AD）相关突变蛋白的小鼠表现出许多该人类疾病的神经病理学和行为特征。已经培育出了在淀粉样前体蛋白（APP）、早老素（PS）1和PS2中表达突变的转基因动物，以及表达不止一种这些突变的动物。例如，在APP小鼠模型中，海马体和大脑皮层中出现与年龄相关的含有β淀粉样蛋白（Aβ）的神经炎性斑块积累，斑块所在区域的星形胶质细胞和小胶质细胞被激活，最终形成斑块的脑区中的胆碱能神经末梢发生退化。APP和PS小鼠模型中缺少神经原纤维缠结以及大脑皮层和皮层下区域（如基底前脑胆碱能和蓝斑去甲肾上腺素能核）的大量神经元丢失。在表达突变tau蛋白的小鼠中可产生神经原纤维缠结，并且在同时表达突变APP的动物中缠结形成会进一步增强。对APP小鼠模型的研究表明，与AD一样，成年海马体神经发生存在异常。AD动物模型已被用于开发和测试降低大脑中Aβ42蛋白水平、神经炎性斑块负荷和胶质细胞激活的治疗方法，并且已经发现一些方法可以恢复学习和记忆功能。如果这些治疗方法能够被证明可以阻止神经退行性过程并恢复海马体神经发生，那么AD患者受损的脑回路可能是可替换的。
