Spatio temporal relationship of pathology and functional decline with tauopathy

tau 蛋白病病理和功能衰退的时空关系

• 批准号: 8473344
• 负责人: Karen Duff
• 金额: $ 5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8473344
• 关键词: Address; Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Area; Biochemical; Blood Volume; Brain; Brain region; Cells; Cerebrum; Cognitive; Data; Dementia; Development; Diagnostic; Disease; Disease Progression; Event; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Hippocampal Formation; Hippocampus (Brain); Human; Impaired cognition; Injection of therapeutic agent; Learning; Lesion; Link; Maps; Measures; Memory; Metabolic; Modeling; Mus; Neocortex; Neurofibrillary Tangles; Neurons; Parietal; Parietal Lobe; Pathology; Pathway interactions; Performance; Progressive Disease; Relative (related person); Secondary to; Staging; Synapses; Tauopathies; Testing; Therapeutic; Time; Transgenes; Transgenic Mice; Transgenic Organisms; area striata; cognitive function; conformer; entorhinal cortex; functional decline; functional disability; hippocampal subregions; insight; interest; mouse model; mutant; neuronal cell body; neuropathology; nonhuman primate; novel; prevent; promoter; public health relevance; tau Proteins; transcytosis; uptake

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.

描述（由申请人提供）：在AD的早期阶段，缠结病理仅限于海马结构。然而，随着疾病的进展，病理学在皮质区域被观察到，这些后期阶段与明显痴呆的发作相关。虽然病理学的进行性传播已经在人类中被绘制出来，但由于使用了在大脑的不适当或区域多样性区域中驱动AD相关转基因高水平表达的启动子，大多数疾病的转基因小鼠模型并没有模拟人类中所见的情况。为了模拟疾病的初始阶段，并绘制病理学在海马结构外的传播，我们创建了一种新的小鼠品系，其在与AD脑中最早受影响区域相关的海马旁/海马区域中具有区域限制的人tau蛋白表达。第二种小鼠模型将通过将含tau的提取物注射到大脑的突触连接和未连接区域来改变tau表达的区域，以允许进一步了解病理传播中网络活性的意义。三个具体的目标将解决以下问题：1）如果病理学在内嗅皮层外的解剖学进展支持tau病理学跨突触传播的假设。2)基础代谢功能时空关系（通过功能成像评估的脑血容量）和病理进展来检验功能下降与病理性tau种类在脆弱脑区域中的积累相关的假设，和3）代谢功能和认知障碍之间的时空关系，以及与病理进展的关系，以检验代谢功能障碍后发生认知障碍的假设，当病理在海马外区域广泛存在时。将评估所有三项指标（神经病理学、代谢功能和认知表现）的相互关系，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学进展并将其与代谢功能（fMRI）和认知表现的功能测量相关联，将深入了解这些测量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，这些治疗方法可以在早期阶段预防疾病的进展。 公共卫生相关性：阿尔茨海默病是一种进行性疾病，其特征在于淀粉样蛋白/Abeta和tau缠结在脑的限定区域中的积累。在早期阶段，缠结病理仅限于海马结构，但随着疾病的进展，病理在皮质区可见，这些后期阶段与明显痴呆的发作相关。虽然病理学的进行性传播已经在人类中被绘制出来，但大多数转基因小鼠模型并没有模拟这种疾病的特征。为了模拟疾病的初始阶段，并绘制病理学，代谢功能障碍和认知障碍在大脑中的传播，我们创造了一种具有区域限制表达人类tau蛋白的新型小鼠系。来自这些小鼠的见解可以为未来的诊断或治疗方法提供信息，这些方法可以防止进展到严重阶段。