NR4A Receptors in Alzheimer's disease

描述（由申请人提供）：阿尔茨海默病（AD）是老年痴呆症的最常见原因，影响全球数百万人。AD病理学包括特征性淀粉样蛋白斑块和由tau组成的神经元缠结，以及在后期阶段的突触丧失和显著的神经变性。AD的主要症状，包括记忆丧失和认知下降，其严重程度与个体经历的神经元损失程度密切相关。我们实验室和其他人以前的工作已经提出，核受体是清除AD小鼠模型中淀粉样蛋白病理和炎症的重要参与者，但核受体在神经变性中的作用尚未得到解决。已知NR的NR 4A亚家族具有神经保护作用，并且NR 4A家族成员Nurr 1（NR 4A 2）和Nur 77（NR 4A 1）的失调与帕金森病和其他神经退行性疾病有关。驱动这一提议的假设是NR 4A失调是AD中神经变性的关键组成部分，并且降低NR 4A表达将对神经元存活产生直接影响。 该提议的一个具体目标是确定在AD小鼠模型中NR 4A表达是否随病理进展而变化。这个问题将使用5XFAD来解决，5XFAD是AD的小鼠模型，其表现出显著的神经元损失，特别是在海马和皮层的V/VI层中。将评估动物在神经变性的不同阶段的总体NR 4A表达，并将评价神经元、小胶质细胞和星形胶质细胞中NR 4A的细胞类型特异性水平以确定贡献细胞类型。该提议的第二个具体目标是确定NR 4A受体的缺失是否加剧AD模型中的神经元死亡。将5XFAD小鼠与Nurr 1条件性无效的小鼠杂交，并评估神经元死亡的严重程度和发作时间的变化。还将使用药理学试剂如RXR激动剂贝沙罗汀在5XFAD小鼠中刺激NR 4A表达，以确定NR 4A是否提供用于治疗AD相关神经变性的潜在治疗靶标。对NR 4A家族NRs在AD中的作用的研究将有助于更好地理解神经元丢失的机制，并可能为AD的治疗提供新的靶点。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia in the elderly and affects millions of people worldwide. AD pathology includes characteristic amyloid plaques and neurofibrillary tangles composed of tau and at later stages synaptic loss and significant neurodegeneration. Major symptoms of AD, including memory loss and cognitive decline, correlate closely in their severity to the degree of neuronal loss an individual experiences. Previous work from our lab and others has proposed that nuclear receptors are important players in the clearance of amyloid pathology and inflammation in AD mouse models, but the role of NRs in neurodegeneration has not yet been addressed. The NR4A subfamily of NRs are known to have neuroprotective effects, and dysregulation of NR4A family members Nurr1 (NR4A2) and Nur77 (NR4A1) is implicated in Parkinson's disease and other neurodegenerative disorders. The hypothesis driving this proposal is that NR4A dysregulation is a key component of neurodegeneration in AD and that decreasing NR4A expression will have a direct impact on neuronal survival. One specific goal of this proposal is to determine if NR4A expression changes with pathological progression in a mouse model of AD. This problem will be addressed using the 5XFAD, a mouse model of AD that exhibits significant neuronal loss, especially in the hippocampus and layers V/VI of the cortex. Animals will be assessed for overall NR4A expression at different stages of neurodegeneration, and cell- type specific levels of NR4As in neurons, microglia, and astrocytes will be evaluated to determine contributing cell types. A second specific goal of this proposal is to determine if the deletion of NR4A receptors exacerbates neuronal death in an AD model. 5XFAD mice will be crossed to mice conditionally null for Nurr1 and assessed for changes in severity and time of onset of neuronal death. NR4A expression will also be stimulated in the 5XFAD mouse using pharmacological agents such as the RXR agonist bexarotene to determine if NR4As provide a potential therapeutic target for treating AD-related neurodegeneration. Characterizing the role of NR4A family NRs in AD will allow for a better understanding of the mechanisms of neuronal loss, and could provide a novel target for therapeutic treatment of AD.