Conditional deletion of Mapt in the adult mouse brain

 描述（由申请人提供）：特定的蛋白质包涵体在病理水平上定义了大多数神经退行性疾病。可溶性到不溶性丝状tau蛋白的转化是许多人类神经变性疾病的核心，所述疾病例如阿尔茨海默病（AD）、额颞叶痴呆和帕金森综合征-17（FTDP-17 T）、皮克病、嗜银颗粒病、皮质基底节变性等。多项研究通过分析与FTDP-17 T相关的Mapt突变来研究tau聚集的生化基础及其在神经退行性疾病中的作用。最近，由于tau蛋白在神经变性中的核心作用以及发现异常tau蛋白通过大脑传播，对tau蛋白靶向治疗的兴趣一直在增长。因此，tau蛋白可能是许多神经退行性疾病的潜在治疗靶点。由于tau聚集在能量上是不利的并且是浓度依赖性的，因此降低tau浓度是一种有吸引力的治疗方法，其可以通过降低tau表达来实现。由于尚未报道条件性Mapt敲除小鼠，因此尚不清楚tau蛋白是否对体内正常神经元功能至关重要，以及成年个体中tau蛋白的减少是否可以良好耐受。本申请中产生的动物模型将允许研究人员解决这个问题，长期目标是通过基于机制的疗法开发某种形式的预防tau蛋白病中的tau蛋白聚集和传播。为了验证我们的假设，我们的具体目标是：具体目标1：产生条件性敲除（cKO）Mapt小鼠，并确定成年小鼠CNS离散细胞群中Mapt基因敲除的后果。我们假设，以潜在的治疗有效的方式降低总体tau蛋白水平可能对tau蛋白病患者有益。已经开发了Mapt的敲除（KO）模型，但是它们显示适应性反应，并且不能用作成年个体中的Mapt KO的模型。我们将产生cKO tau小鼠，并首次使用我们的“floxed”Mapt小鼠与在特异性启动子控制下表达CreERT 2蛋白的转基因小鼠组合，研究成年小鼠体内tau功能丧失的生物学后果。这种方法特别有吸引力，因为小鼠将仅在期望的时间/脑区域具有等位基因缺失，这可以避免混淆问题，例如发育补偿。这些动物将允许测试通过大脑的异常tau传播，以及旨在减少（或消除）tau表达的治疗方法是否是tau蛋白病患者的可行方法。

 DESCRIPTION (provided by applicant): Specific protein inclusions define most neurodegenerative diseases at the pathological level. The conversion of soluble to insoluble filamentous tau protein is central to many human neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia and parkinsonism-17 (FTDP-17T), Pick disease, Argyrophilic grain disease, Corticobasal degeneration, among many others. Multiple studies have looked at the biochemical basis of tau aggregation and its role in neurodegenerative diseases by analyzing Mapt mutations associated with FTDP-17T. More recently, an interest in tau-targeted treatments has been growing because of the central role of tau in neurodegeneration and the discovery of abnormal tau propagation through the brain. Therefore, tau may be an excellent potential therapeutic target for many neurodegenerative diseases. Since tau aggregation is energetically unfavorable and concentration dependent, a reduction of tau concentration is an attractive treatment approach that might be achieved through decreased tau expression. As no conditional Mapt knockout mice have yet been reported, it is unclear if tau is critical for normal neuronal function in vivo, and whether reducton of tau in adult individuals may be well tolerated. The animal models generated in this application will allow investigators to solve this problem, with the long term goal of developing some form of prevention of tau aggregation and propagation in tauopathies by a mechanism-based therapy. In order to test our hypothesis, our specific aims are: Specific Aim 1: To generate conditionally knock-out (cKO) Mapt mice, and determine the consequences of Mapt gene knock-out in discrete cell populations of the CNS of adult mice. We hypothesize that lower overall tau protein levels in a potentially therapeutically productive way may be beneficial for patients with tauopathies. Knock-out (KO) models of Mapt have been developed, but they show adaptive responses, and cannot be used as models for Mapt KO in adult individuals. We will generate cKO tau mice and investigate for the first time the biological consequences of the loss of function of tau in vivo in adult mice using our "floxed" Mapt mice in combination with transgenic mice expressing the CreERT2 protein under the control of specific promoters. This approach is particularly appealing since the mice will have allele deletion only at the desired time/brain area which may avoid confounding issues such as developmental compensation. These animals will allow the testing of abnormal tau propagation through the brain and whether therapeutic approaches aimed at reducing (or eliminating) tau expression are viable approaches for patients with tauopathies.