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: 8133243
• 负责人: Karen Duff
• 金额: $ 45.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133243
• 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; 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的最早阶段，Tangle病理学仅限于海马形成。然而，随着疾病的发展，病理学在皮质区域，这些阶段与明显的痴呆症的发作有关。尽管病理的进行性逐渐扩散已在人类中映射，但大多数疾病的转基因小鼠模型并未建模由于使用启动子在不适当或区域多样的地区驱动高水平表达的启动子而引起的。大脑。为了模拟该疾病的初始阶段，并将病理从海马形成中绘制出来，我们创建了一条新型的小鼠系，在帕拉希公平/海马区域与最早受影响区域的帕拉希公平/海马区域中人类Tau的区域表达受到区域限制。广告大脑。第二个小鼠模型将通过将含Tau提取物注入突触连接的区域以及大脑的未连接区域来改变TAU的区域，以便进一步深入了解网络活动在病理传播中的重要性。三个具体目的将解决以下问题1）如果病理学的解剖学进展从内hin骨皮质中脱离，则支持tau病理透射传播的假设。 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，以检验功能下降与弱势脑区域中病理tau物种的积累相关的假设，3）在代谢功能和认知障碍之间以及与病理进展的关系，以检验代谢功能障碍后认知障碍发生的假设，当时病理在公寓外区域广泛。将对所有三种措施（神经病理学，代谢功能和认知表现）进行评估，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病理生物学中的关键问题 - 透射性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）和认知性能的功能指标相关。将深入了解这些措施之间的时空关系。这些见解可以告知未来的治疗方法，这些方法可能会在早期阶段进行治疗。 公共卫生相关性：阿尔茨海默氏病是一种进行性疾病，其特征是淀粉样蛋白/ABETA和Tau Tangles在确定的大脑区域中的积累。在最早的阶段，缠结病理学仅限于海马形成，但随着疾病的发展，病理学在皮质区域，这些后期阶段与明显的痴呆症的发作相关。尽管病理学的逐渐扩散已在人类中绘制，但大多数疾病的转基因小鼠模型并未对该疾病的这一特征进行建模。为了模拟该疾病的初始阶段，并绘制了通过大脑的病理，代谢功能障碍和认知障碍的传播，我们创建了一条新型小鼠，具有人类TAU的区域限制。这些小鼠的见解可以告知未来的诊断或治疗方法，这些方法可以防止进展到严重的阶段。