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

基本信息

批准号：
8534504
负责人：
Karen Duff
金额：
$ 35万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/8534504
关键词：
Affect Age Alzheimer&apos 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 Health 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 synaptic function tau Proteins tau aggregation

项目摘要

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（NFTS）始于反式/内嗅皮层（EC）区域，并扩散到大脑的神经解剖学上。 tau病理学的阶段从第I阶段到VI（Braak，H。和Braak，E。（1991）。阶段I和II阶段与临床前的AD和变化相关，这些变化在很大程度上局限于跨内术皮层的上层（跨性别阶段）（跨性别阶段）。涉及阶段和IV阶段III和IV阶段。跨性别区域和内him骨区域，海马和几个皮层核（边缘阶段）的特征是新皮质关联区域的神经纤维病理学广泛的特征。靶向tau可能是一种良好的治疗策略。引人注目的观察结果是，人类可以将突触穿过单突触连接的细胞（“下游”或“次级”电路），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途径。为了开始了解tauopathy如何繁殖，我们需要了解细胞生物学的新方面相对于tau。我们建议，随着tauopathy的恶化，tau被释放到细胞外空间中，因此可以被相邻的细胞吸收。进入内部后，可能会发生模板到内源性tau，从而使过程永久化。在AIM 1中，我们将执行一个仔细的时间，以量化具有病理TAU分布的突触前后标记，以评估原发性和次级电路中事件的顺序。在AIM 2中，为了理解Tauopathy恶化的功能后果，尤其是在次级电路上，我们将监视通过电生理学评估的“细胞行为”读数分子，ARC和突触功能。在AIM 3中，我们将开发一个极化的细胞培养模型，以研究TAU构象的积累如何影响病理学的传播，从体内室室（跨神经元传播）或轴突室（跨突触传播）。在AIM 4.1中，我们将测试一种治疗方法，使用抗TAU抗体MC1的免疫疗法是否可以防止EC-TAU小鼠系中的Tauopathy细胞传播细胞，并且在AIM 4.2中，我们将评估扭曲的衰减与改善的结构和功能相关。