NR4A Receptors in Alzheimer's disease

描述（由申请人提供）：阿尔茨海默病（AD）是老年人痴呆症的最常见原因，影响着全世界数百万人。阿尔茨海默病的病理包括特征性的淀粉样斑块和由tau蛋白组成的神经原纤维缠结，并在后期出现突触丧失和显著的神经变性。阿尔茨海默病的主要症状，包括记忆丧失和认知能力下降，其严重程度与个体经历的神经元丧失程度密切相关。我们实验室和其他人之前的工作已经提出，在AD小鼠模型中，核受体在清除淀粉样蛋白病理和炎症方面发挥重要作用，但nr在神经退行性变中的作用尚未得到解决。已知nrrs的NR4A亚家族具有神经保护作用，NR4A家族成员Nurr1 （NR4A2）和Nur77 （NR4A1）的失调与帕金森病和其他神经退行性疾病有关。该建议的假设是NR4A失调是AD神经退行性变的关键组成部分，NR4A表达降低将直接影响神经元存活。该提案的一个具体目标是确定NR4A表达是否随着AD小鼠模型的病理进展而改变。这个问题将使用5XFAD来解决，5XFAD是一种阿尔茨海默病的小鼠模型，它表现出明显的神经元损失，特别是在海马和皮层的V/VI层。研究人员将评估动物在神经退行性变不同阶段的总体NR4A表达，并评估神经元、小胶质细胞和星形胶质细胞中NR4A的细胞类型特异性水平，以确定起作用的细胞类型。该建议的第二个具体目标是确定NR4A受体的缺失是否会加剧AD模型中的神经元死亡。将5XFAD小鼠与Nurr1条件无效的小鼠杂交，评估神经元死亡的严重程度和发生时间的变化。使用RXR激动剂贝沙罗汀等药物刺激5XFAD小鼠的NR4A表达，以确定NR4A是否为治疗ad相关神经变性提供了潜在的治疗靶点。研究NR4A家族NRs在AD中的作用将有助于更好地理解神经元丢失的机制，并为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.