Benveniste Helene, Ma Yu, Dhawan Jasbeer, Gifford Andrew, Smith S David, Feinstein Igor, Du Congwu, Grant Samuel C, Hof Patrick R
Brookhaven National Laboratory, Medical Department, Bldg. 490, 30 Bell Avenue, Upton, NY 11973, USA.
Ann N Y Acad Sci. 2007 Feb;1097:12-29. doi: 10.1196/annals.1379.006.
The wide variety of transgenic mouse models of Alzheimer's disease (AD) reflects the search for specific genes that influence AD pathology and the drive to create a clinically relevant animal model. An ideal AD mouse model must display hallmark AD pathology such as amyloid plaques, neurofibrillary tangles, reactive gliosis, dystrophic neurites, neuron and synapse loss, and brain atrophy and in parallel behaviorally mimic the cognitive decline observed in humans. Magnetic resonance (MR) microscopy (MRM) can detect amyloid plaque load, development of brain atrophy, and acute neurodegeneration. MRM examples of AD pathology will be presented and discussed. What has lagged behind in preclinical research using transgenic AD mouse models is functional phenotyping of the brain; in other words, the ability to correlate a specific genotype with potential aberrant brain activation patterns. This lack of information is caused by the technical challenges involved in performing functional MRI (fMRI) in mice including the effects of anesthetic agents and the lack of relevant "cognitive" paradigms. An alternative approach to classical fMRI using external stimuli as triggers of brain activation in rodents is to electrically or pharmacologically stimulate regions directly while simultaneously locally tracking the activated interconnected regions of rodents using, for example, the manganese-enhanced MRI (MEMRI) technique. Finally, transgenic mouse models, MRM, and future AD research would be strengthened by the ability to screen for AD-like pathology in other non-AD transgenic mouse models. For example, molecular biologists may focus on cardiac or pulmonary pathologies in transgenic mice models and as an incidental finding discover behavioral AD phenotypes. We will present MRM data of brain and cardiac phenotyping in transgenic mouse models with behavioral deficits.
阿尔茨海默病（AD）转基因小鼠模型种类繁多，这反映了人们对影响AD病理的特定基因的探索，以及创建具有临床相关性动物模型的驱动力。理想的AD小鼠模型必须表现出AD的标志性病理特征，如淀粉样斑块、神经原纤维缠结、反应性胶质增生、营养不良性神经突、神经元和突触丧失以及脑萎缩，同时在行为上模拟人类观察到的认知衰退。磁共振（MR）显微镜（MRM）可以检测淀粉样斑块负荷、脑萎缩的发展以及急性神经退行性变。将展示并讨论AD病理的MRM实例。在使用转基因AD小鼠模型的临床前研究中落后的是大脑的功能表型分析；换句话说，就是将特定基因型与潜在异常脑激活模式相关联的能力。这种信息的缺乏是由在小鼠中进行功能磁共振成像（fMRI）所涉及的技术挑战导致的，包括麻醉剂的影响以及缺乏相关的“认知”范式。一种不同于使用外部刺激作为啮齿动物脑激活触发因素的经典fMRI的替代方法是直接电刺激或药理刺激区域，同时使用例如锰增强磁共振成像（MEMRI）技术在局部追踪啮齿动物激活的相互连接区域。最后，如果能够在其他非AD转基因小鼠模型中筛选出类似AD的病理特征，将加强转基因小鼠模型、MRM和未来的AD研究。例如，分子生物学家可能专注于转基因小鼠模型中的心脏或肺部病理，作为偶然发现发现行为性AD表型。我们将展示具有行为缺陷的转基因小鼠模型中脑和心脏表型分析的MRM数据。
