Propagation of tauopathy: role of degeneration and impact of immunotherapy

tau 蛋白病的传播：变性的作用和免疫治疗的影响

• 批准号: 8705062
• 负责人: Karen Duff
• 金额: $ 34.65万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705062
• 关键词: Affect; Age; Alzheimer' s Disease; Antibodies; Area; Axon; Axonal Transport; Back; Behavior; Biological Models; Brain; Brain region; Cell Count; Cell Culture Techniques; Cell Death; Cell Nucleus; Cell model; Cells; Cellular biology; Cessation of life; Coculture Techniques; Data; Deafferentation procedure; Dementia; Disease; Electrophysiology (science); Event; Extracellular Space; Functional disorder; Genes; Hippocampal Formation; Hippocampus (Brain); Human; Immunotherapy; Impaired cognition; Lead; Link; Maps; Measures; Messenger RNA; Microfluidics; Mitochondria; Modeling; Monitor; Mus; Neocortex; Neurofibrillary Tangles; Neurons; Organelles; Outcome Measure; Pathology; Pathway interactions; Perforant Pathway; Presynaptic Terminals; Process; Publishing; Role; Route; Staging; Structure of molecular layer of cerebellar cortex; Synapses; Synaptic plasticity; Tauopathies; Testing; Therapeutic; Therapeutic Agents; Thioflavin S; Transgenic Mice; attenuation; base; clinically relevant; conformer; dentate gyrus; entorhinal cortex; functional decline; functional outcomes; granule cell; improved; in vitro Model; in vivo; interest; mild cognitive impairment; mouse model; neocortical; neurofibrillary tangle formation; neuronal cell body; novel; polarized cell; postsynaptic; pre-clinical; presynaptic; prevent; public health relevance; synaptic function; tau Proteins; tau aggregation

DESCRIPTION (provided by applicant): In AD, neurofibrillary pathology (NFTs) starts in the trans/entorhinal cortex (EC) area and spreads to neuroanatomically connected areas of the brain. The ''Braak" stages of tau pathology go from stages I to VI (Braak, H. and Braak, E. (1991). Stages I and II correlate with preclinical AD and alterations that are largely confined to the upper layers of the transentorhinal cortex (transentorhinal stages). Stages III and IV correlate with mild cognitive impairment and are characterized by robust involvement of the transentorhinal and entorhinal regions, with a less severe involvement of the hippocampus and several subcortical nuclei (limbic stages). Stages V-VI are characterized by extensive neurofibrillary pathology in neocortical association areas (isocortical stages) and a further increase in pathology in the brain regions affected during stages I-IV. As tangle pathology correlates well with cognitive impairment, targeting tau may be a good therapeutic strategy. To explore why tauopathy maps the way it does in the brain we created a mouse model of the earliest Braak stages of AD (Liu et. al. 2012). Our new transgenic mouse model (line EC-tau) has predominant EC expression of pathological tau, and it replicates the spatio-temporal aspects of tauopathy in the AD brain. Of significant interest was the observation that human tau could cross a synapse into monosynaptically connected cells ("downstream" or "secondary" circuits), which explains how pathology may propagate through the brain, and why it follows a trans-synaptic route. To begin to understand how tauopathy propagates, we need to understand new aspects of cellular biology with respect to tau. We propose that as tauopathy worsens, tau is released into the extracellular space from whence it could be taken up by adjacent cells. Once inside, templating to endogenous tau is likely to occur allowing the process to perpetuate. In aim 1 we will perform a careful timecourse quantifying pre and post synaptic markers with pathological tau distribution to assess the order of events in primary and secondary circuits. In aim 2, to understand the functional consequences of worsening tauopathy, especially on secondary circuits, we will monitor the "cellular behavior" readout molecule, Arc, and synaptic function, assessed by electrophysiology. In aim 3 we will develop a polarized cell culture model to study how the accumulation of tau conformers impacts pathology propagation from the somatodendritic compartments (transneuronal propagation) or the axonal compartment (trans-synaptic propagation). In aim 4.1 we will test whether a therapeutic approach, immunotherapy using the anti-tau antibody MC1 can prevent cell to cell propagation of tauopathy in the EC-tau mouse line, and in aim 4.2, we will assess whether attenuation of tauopathy correlates with improved structural and functional outcomes.

描述（由申请人提供）：在 AD 中，神经原纤维病理学 (NFT) 始于跨/内嗅皮层 (EC) 区域，并扩散到大脑的神经解剖学连接区域。 tau 病理学的“Braak”阶段从 I 期到 VI 期（Braak, H. 和 Braak, E. (1991)）。I 期和 II 期与临床前 AD 和主要局限于经内嗅皮层上层的改变相关（经内嗅期）。III 期和 IV 期与轻度认知障碍相关，其特征是认知障碍的强烈参与。 经内嗅区和内嗅区，海马体和几个皮质下核（边缘阶段）受累程度较轻。 V-VI期的特征是新皮质关联区（等皮质期）广泛的神经原纤维病理学，以及I-IV期受影响的大脑区域的病理学进一步增加。由于缠结病理学与认知障碍密切相关， 靶向 tau 蛋白可能是一种很好的治疗策略。为了探究 tau 蛋白病在大脑中的分布方式，我们创建了 AD 早期 Braak 阶段的小鼠模型（Liu et. al. 2012）。我们的新转基因小鼠模型（EC-tau 系）具有病理性 tau 的主要 EC 表达，并且它复制了 AD 大脑中 tau 病的时空方面。值得注意的是观察 人类 tau 蛋白可以穿过突触进入单突触连接的细胞（“下游”或“次级”回路），这解释了病理学如何通过大脑传播，以及为什么它遵循跨突触路线。为了开始了解 tau 蛋白病如何传播，我们需要了解细胞生物学中有关 tau 蛋白的新方面。我们建议，随着 tau 蛋白病恶化，tau 蛋白被释放到 细胞外空间，从那里它可以被相邻细胞占据。一旦进入内部，内源性 tau 蛋白的模板化就可能发生，从而使该过程得以延续。在目标 1 中，我们将执行仔细的时间过程，量化具有病理 tau 分布的突触前和突触后标记，以评估初级和次级回路中的事件顺序。在目标 2 中，为了了解恶化的 tau 蛋白病的功能后果，特别是在二级回路上，我们 将监测“细胞行为”读出分子、Arc 和突触功能，并通过电生理学进行评估。在目标 3 中，我们将开发一个极化细胞培养模型来研究 tau 构象异构体的积累如何影响体细胞树突区室（跨神经元传播）或轴突区室（跨突触传播）的病理传播。在目标 4.1 中，我们将测试治疗是否有效 方法，使用抗 tau 抗体 MC1 的免疫疗法可以防止 EC-tau 小鼠系中 tau 蛋白病的细胞间传播，在目标 4.2 中，我们将评估 tau 蛋白病的减弱是否与结构和功能结果的改善相关。