Propagation of tauopathy: role of degeneration and impact of immunotherapy

描述(申请人提供)：在AD中，神经纤维病理学(NFTs)始于经/内嗅皮层(EC)区域，并扩散到大脑的神经解剖学连接区域。Tau病理的‘’Braak‘阶段从第一阶段到第六阶段(Braak，H.和Braak，E.(1991))。I期和II期与临床前AD和主要局限于经鼻鼻皮质上层的改变相关(经鼻鼻阶段)。III和IV期与轻度认知损害相关，其特点是经鼻和内嗅区的强烈受累，而海马体和几个皮质下核团(边缘期)的受累较轻。V-VI期的特点是新皮质联合区域(等皮质期)广泛的神经原纤维病变，I-IV期受影响的脑区病理进一步增加。由于缠结的病理与认知损害密切相关，靶向tau可能是一个很好的治疗策略。为了探索为什么牵张症在大脑中的映射方式，我们创建了AD早期Braak阶段的小鼠模型(Liu et.艾尔2012年)。我们的新的转基因小鼠模型(EC-tau)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，观察到人类tau可以穿过突触进入单突触连接的细胞(“下游”或“二级”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的路线。为了开始了解tau疗法是如何传播的，我们需要了解与tau相关的细胞生物学的新方面。我们认为，随着tau病的恶化，tau被释放到细胞外空间，从那里它可以被相邻的细胞占据。一旦进入内部，很可能会发生内源性tau的模板化，从而使这一过程得以延续。在目标1中，我们将用病理tau分布来量化突触前和突触后的标记物，以评估初级和次级回路中事件的顺序。在目标2中，为了了解肌张力障碍恶化的功能后果，特别是对二级回路的影响，我们将监测“细胞行为”读出分子Arc和突触功能，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，以研究tau构象的积累如何影响来自躯体树突间(跨神经元传播)或轴突间(跨突触传播)的病理传播。在目标4.1中，我们将测试一种治疗方法，即使用抗tau抗体MC1的免疫疗法是否可以阻止EC-tau小鼠品系中tau病的细胞间传播，并在目标4.2中，我们将评估tau病的减弱是否与结构和功能结果的改善相关。

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.