Propagation of tauopathy: role of degeneration and impact of immunotherapy

描述（由申请人提供）：在AD中，神经病理学（NFT）始于跨/内嗅皮质（EC）区域，并扩散至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年）。I期和II期与临床前AD和主要局限于经内嗅皮质上层的改变（经内嗅期）相关。III期和IV期与轻度认知障碍相关，其特征在于经内嗅区和内嗅区的强烈参与，海马和几个皮质下核的参与程度较低（边缘系统阶段）。阶段V-VI的特征在于新皮质联合区（等皮质阶段）中广泛的神经病理学，以及在阶段I-IV期间受影响的脑区域中病理学的进一步增加。由于缠结病理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。为了探索为什么tau蛋白病以其在大脑中的方式映射，我们创建了AD的最早Braak阶段的小鼠模型（Liu et. 2012）。我们的新的转基因小鼠模型（系EC-tau）具有病理性tau的主要EC表达，并且它复制了AD脑中tau病变的时空方面。重要的是观察到人类tau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蛋白病是如何传播的，我们需要了解与tau蛋白有关的细胞生物学的新方面。我们认为，随着tau蛋白病的发展，tau蛋白被释放到细胞外空间，从那里它可以被相邻的细胞吸收。一旦进入，内源性tau的模板可能会发生，从而使该过程得以延续。在目标1中，我们将进行仔细的时间过程，量化具有病理性tau分布的突触前和突触后标记物，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tau蛋白病恶化的功能后果，特别是在次级回路上，我们将监测通过电生理学评估的“细胞行为”读出分子Arc和突触功能。在目标3中，我们将开发极化细胞培养模型以研究tau构象异构体的积累如何影响从体树突隔室（跨神经元传播）或轴突隔室（跨突触传播）的病理传播。在目标4.1中，我们将测试治疗方法，使用抗tau抗体MC 1的免疫疗法是否可以防止EC-tau小鼠系中tau病变的细胞间传播，并且在目标4.2中，我们将评估tau病变的减弱是否与改善的结构和功能结果相关。

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.