Spatio temporal relationship of pathology and functional decline with tauopathy

描述(申请人提供)：在AD的早期阶段，缠绕病理仅限于海马结构。然而，随着疾病的发展，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。尽管病理学在人类中的逐渐传播已经被绘制出来，但大多数这种疾病的转基因小鼠模型并没有模拟在人类中看到的情况，这是因为使用了启动子来驱动AD相关转基因在不适当的或区域不同的大脑区域高水平表达。为了对疾病的早期阶段进行建模，并绘制出病理从海马结构向外扩散的图谱，我们创建了一个新的小鼠品系，该品系在海马旁/海马区具有人tau的区域受限表达，与AD大脑中最早受影响的区域相关。第二种小鼠模型将通过将含有tau的提取物注射到大脑的突触连接和不连接区域来改变tau表达的区域，以进一步了解网络活动在病理传播中的重要性。三个具体的目标将解决以下问题：1)如果内嗅皮层的病理解剖进展支持tau病理跨突触传播的假设。2)基础代谢功能(功能成像评估的脑血流量)与病理进展的时空关系，以验证功能衰退与病理tau类物质在脆弱脑区聚集有关的假说；3)代谢功能与认知损害的时空关系，以及与病理进展的关系，以检验当病理广泛存在于海马区时，代谢功能障碍后发生认知损害的假说。所有这三项指标(神经病理、代谢功能和认知表现)都将进行相对评估，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AD病理生物学中的一个关键问题-跨突触扩散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)和认知表现的功能指标相关联将有助于深入了解这些指标之间的空间和时间关系。这些见解可以为未来的治疗方法提供信息，如果在早期给予治疗，可以防止疾病的进展。 与公共卫生相关：阿尔茨海默病是一种进行性疾病，其特征是淀粉样蛋白/Abeta和tau蛋白在大脑的特定区域积累。在早期阶段，缠绕病理仅限于海马体结构，但随着疾病的发展，病理可见于皮质区域，这些后期与明显痴呆的发病相关。虽然病理的逐渐传播在人类中已经被绘制出来，但大多数转基因小鼠的疾病模型并不模拟疾病的这一特征。为了模拟疾病的初始阶段，并绘制病理、代谢功能障碍和认知障碍通过大脑的传播图，我们创建了一种新的小鼠系，其人tau的表达受到区域限制。来自这些小鼠的见解可能会为未来的诊断或治疗方法提供信息，这些方法可能会防止病情发展到严重阶段。

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.