Hippocampal Microstructure and Function in APP Tg Mice

我们建议对过度表达突变的人类淀粉样前体蛋白基因的小鼠的生化、微结构、功能和行为变化进行纵向研究，以发现对认知能力下降至关重要的早期变化。这项研究将在预定年龄检测杂合子Tg2576和PDAPP小鼠，从很小的年龄开始，贯穿它们的整个生命周期。非转基因窝产仔将作为对照。海马区CA1和CA3区、齿状回以及连接的皮质和皮质下结构的完整对记忆和学习至关重要。我们假设，由于Aβ性质的变化，海马区神经元组件的细胞结构发生了微妙的变化。在发展中的Aβ病理中，结构变化先于淀粉样蛋白沉积。反映在水的自扩散特性中的微观结构变化将使用具有高空间分辨率的在体扩散张量磁共振成像来测量。将计算感兴趣区域的分数各向异性。将进行形态计量学分析，以研究扩散各向异性变化的细胞学基础。洗涤剂可溶和洗涤剂不溶Aβ的测量将遵循Aβ的病理过程。在对Tg2576小鼠的初步实验中，我们发现24周龄小鼠的齿状回和CA3区的各向异性分数显著低于对照组小鼠，这是在APP转基因小鼠海马区观察到的最早的变化之一。在12周大的时候，转基因小鼠和对照小鼠表现出相似的扩散特征。我们进一步假设，Aβ引起的海马区微结构变化可能损害海马区的功能，进而导致行为障碍。在开阔的场地中运动时，通过记录海马背上方区域theta带上的磁场振荡，可以测量到海马区电路功能的中断。将使用Morris水迷宫任务来测量小鼠执行海马区依赖任务的能力。这项拟议的研究将确定早期受发展中的Aβ病理影响的海马区和相关的皮质和皮质下结构。这些信息可能有助于制定治疗阿尔茨海默病的策略。研究计划的纵向设计将最大限度地减少可能影响横断面研究的个体差异和队列效应。

We propose a longitudinal study of biochemical, microstructural, functional and behavioral changes in mice overexpressing mutant human amyloid precursor protein genes in order to detect early changes that are critical to cognitive decline. The study will examine heterozygous Tg2576 and PDAPP mice at pre-determined ages, from a very young age over their entire lifespan. Non-transgenic littermates will be used as controls. The integrity of the hippocampal subfields CA1 and CA3, dentate gyrus, and connected cortical and subcortical structures of the hippocampal circuit is crucial for memory and learning. We hypothesize subtle changes occur in the cytoarchitecture of the neuronal assemblies in the hippocampal circuit as a result of the changing nature of Aβ. Structural changes precede amyloid deposition in the developing Aβ pathology. Microstructural changes, reflected in water self-diffusion characteristics, will be measured using in vivo diffusion tensor MR imaging with high spatial resolution. Fractional anisotropy will be calculated for the regions of interest. Morphometric analysis will be carried out to investigate the cytological basis for changes in diffusion anisotropy. Detergent soluble and detergent insoluble Aβ will be measured to follow the course of Aβ pathology. In preliminary experiments on Tg2576 mice, we have found significant reduction in fractional anisotropy in dentate gyrus and CA3 subfield of 24-week old mice relative to control mice, one of the earliest changes observed in the hippocampus in APP transgenic mice. At 12 weeks of age, transgenic and control mice exhibited similar diffusion characteristics. We further hypothesize that Aβ induced microstructural changes to the hippocampal regions are likely to compromise hippocampal function and in turn lead to deficits in behavior. Disruption in the function of the hippocampal circuit will be measured by recording field oscillations at the theta band in the area over the dorsal hippocampus during locomotion in an open field. The ability of the mice to perform hippocampally-dependent tasks will be measured using the Morris water maze task. The proposed study will identify the hippocampal subdivisions and related cortical and subcortical structures that are affected early by the developing Aβ pathology. Such information could be useful for developing therapeutic strategies for the treatment of AD. The longitudinal design of the research plan will minimize individual differences and cohort effects that may affect cross-sectional studies.