Spatio temporal relationship of pathology and functional decline with tauopathy

描述（由申请人提供）：在AD的早期阶段，缠结病理仅限于海马形成。然而，随着疾病的进展，病理出现在皮质区域，这些后期阶段与显性痴呆的发病相关。尽管病理的逐渐传播已经在人类中被描绘出来，但大多数这种疾病的转基因小鼠模型并不能模拟在人类中看到的情况，因为在不适当的或区域不同的大脑区域中使用了驱动ad相关转基因高水平表达的启动子。为了模拟疾病的初始阶段，并绘制出病理在海马体形成外的扩散图，我们创建了一种新的小鼠系，在与阿尔茨海默病大脑最早受影响区域相关的海马体旁/海马体区域中，人类tau蛋白的区域表达受到限制。第二个小鼠模型将通过将含有tau的提取物注射到突触连接和非连接的大脑区域来改变tau表达的区域，从而进一步了解网络活动在病理传播中的重要性。三个特定的目标将解决以下问题1)如果病理的解剖进展从内嗅皮层支持tau病理跨突触传播的假设。2)基础代谢功能（通过功能成像评估的脑血容量）与病理进展之间的时空关系，以验证功能下降与脑易损区病理性tau物质积累相关的假设；3)代谢功能与认知障碍之间的时空关系；以及与病理进展的关系来验证认知障碍发生在代谢功能障碍之后的假设，当病理在海马外区域广泛存在时。所有三项措施（神经病理学，代谢功能和认知表现）将相互评估，以提供事件的空间和时间顺序。这些研究将使我们不仅能够解决阿尔茨海默病病理生物学中的一个关键问题——跨突触传播是否与疾病的传播有关，而且绘制疾病的解剖进展图，并将其与代谢功能（fMRI）和认知表现的功能测量相关联，将使我们深入了解这些测量之间的时空关系。这些见解可以为未来的治疗方法提供信息，这些方法可以在早期给药时防止疾病的进展。

DESCRIPTION (provided by applicant): In the earliest stages of AD, tangle pathology is limited to the hippocampal formation. As the disease progresses however, pathology is seen in cortical areas and these later stages correlate with the onset of overt dementia. Although the progressive spread of pathology has been mapped in humans, most transgenic mouse models of the disease do not model what is seen in humans due to the use of promoters that drive high level expression of AD-related transgenes in inappropriate, or regionally diverse areas of the brain. To model the initial stages of the disease, and to map the spread of pathology out of the hippocampal formation, we have created a novel line of mice with regionally restricted expression of human tau in parahippocampal/hippocampal regions of relevance to the earliest affected regions in the AD brain. A second mouse model will change the regions in which tau is expressed through injection of tau-containing extract into synaptically connected, and unconnected areas of the brain to allow further insight into the significance of network activity in pathology propagation. Three specific aims will address the following issues 1) if the anatomical progression of pathology out of the entorhinal cortex supports the hypothesis that tau pathology spreads transynaptically. 2) the spatio-temporal relationship between basal metabolic function (cerebral blood volume assessed by functional imaging) and pathological progression to test the hypothesis that functional decline is associated with accumulation of pathological tau species in vulnerable brain regions and 3) the spatio-temporal relationship between metabolic function and cognitive impairment, and the relationship with pathological progression to test the hypothesis that cognitive impairment occurs after metabolic dysfunction, when pathology is extensive in extrahippocampal regions. All three measures (neuropathology, metabolic function and cognitive performance) will be assessed relative to each other to provide a spatial and temporal ordering of events. These studies will allow us to not only address a key issue in AD pathobiology - whether transynaptic spread is implicated in propagation of the disease, but mapping the anatomical progression of the disease and correlating it with functional measures of metabolic function (fMRI) and cognitive performance will give insight into spatial and temporal relationships between these measures. These insights could inform on future therapeutic approaches that could prevent the progression of the disease when administered at an early stage. PUBLIC HEALTH RELEVANCE: Alzheimer's Disease is a progressive disease characterized by the accumulation of amyloid/Abeta and tau tangles in defined regions of the brain. In the earliest stages, tangle pathology is limited to the hippocampal formation but as the disease progresses, pathology is seen in cortical areas and these later stages correlate with the onset of overt dementia. Although the progressive spread of pathology has been mapped in humans, most transgenic mouse models of the disease do not model this feature of the disease. To model the initial stages of the disease, and to map the spread of pathology, metabolic dysfunction and cognitive impairment through the brain, we have created a novel line of mice with regionally restricted expression of human tau. Insights from these mice could inform on future diagnostic or therapeutic approaches that could prevent the progression to severe stages.