Hippocampal Microstructure and Function in APP Tg Mice

我们建议对过度表达人类淀粉样前体蛋白突变基因的小鼠进行生化、微观结构、功能和行为变化的纵向研究，以发现对认知能力下降至关重要的早期变化。该研究将在预先确定的年龄检查杂合子Tg2576和PDAPP小鼠，从很小的时候开始，在它们的整个生命周期中。非转基因幼崽将被用作对照。海马体CA1和CA3亚区、齿状回以及连接海马体回路的皮层和皮层下结构的完整性对记忆和学习至关重要。我们假设，由于a β性质的改变，海马回路中神经元组装的细胞结构发生了微妙的变化。在发展中的Aβ病理中，结构改变先于淀粉样蛋白沉积。微观结构的变化，反映在水的自扩散特性，将测量体内扩散张量磁共振成像具有高空间分辨率。将计算感兴趣区域的分数各向异性。形态学分析将用于研究扩散各向异性变化的细胞学基础。测定洗涤剂可溶性和洗涤剂不溶性Aβ，以跟踪Aβ病理过程。在Tg2576小鼠的初步实验中，我们发现24周龄小鼠齿状回和CA3亚场的各向异性分数明显降低，这是APP转基因小鼠海马最早观察到的变化之一。在12周龄时，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诱导的海马区域微结构变化可能会损害海马功能，进而导致行为缺陷。海马回路功能的中断将通过记录在开阔场地运动时海马背侧区域的θ波段的场振荡来测量。小鼠执行海马体依赖性任务的能力将通过Morris水迷宫任务来测量。该研究将确定早期受Aβ病理影响的海马分支和相关皮层和皮层下结构。这些信息可能有助于制定治疗AD的治疗策略。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.