The role of fractalkine signaling in neurodegenerative 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，目前是美国第七大死因。阿尔茨海默病的特征和诊断是通过明显的神经病理改变，包括细胞外ß-淀粉样蛋白（ß）肽沉积，神经元中微管相关蛋白tau （MAPT）的细胞内聚集和明显的神经炎症。类似地，在非阿尔茨海默病中，也有丰富的MAPT病理和神经炎症。然而，神经炎症与各种脑部病理之间的确切机制关系尚不清楚。最近的研究表明，通过fractalkine受体（CX3CR1）的神经元-小胶质信号传导参与神经保护和神经变性。为了研究CX3CL1-CX3CR1信号在阿尔茨海默病和非阿尔茨海默病中的作用，我们进行了初步研究，以研究CX3CR1缺乏对asas和MAPT病理的影响。值得注意的是，在两种不同的AD小鼠模型中，CX3CR1缺陷导致与小胶质细胞激活改变相关的asb病理减少，而相反，在MAPT病理hTau小鼠模型中，CX3CR1缺陷导致小胶质细胞激活、MAPT磷酸化和聚集增强以及行为障碍。在asas和MAPT模型中的进一步研究表明，IL1信号可能有助于AD脑病理中CX3CR1依赖性改变。当前研究中需要验证的假设是，神经元释放的可溶性CX3CL1向小胶质细胞内的CX3CR1发出信号，并通过与il - 1有关的机制，通过阻断小胶质细胞对ß的吞噬去除和减少神经元内MAPT的磷酸化和聚集，在AD表型中发挥独特的作用。这些研究将利用最先进的asas和MAPT病理小鼠模型，以及CXC3CR1敲除小鼠和CX3CL1敲除小鼠和转基因小鼠来检查生物化学，基因表达，神经病理学和行为的影响。本建议的具体目标是：1。确定CX3CL1-CX3CR1信号在小鼠asb沉积模型中的作用。确定CX3CL1-CX3CR1信号在MAPT病理小鼠模型中的作用。确定IL1信号在AD病理中CX3CR1依赖性改变中的作用。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD), the most common cause of dementia in the elderly, is now the seventh major cause of death in the United States. AD is characterized and diagnosed by distinctive neuropathological alterations including extracellular deposits of the ß-amyloid (Aß) peptide, intracellular aggregates of the microtubule associated protein tau (MAPT) in neurons and marked neuroinflammation. Similarly in non-AD tauopathies, there is both abundant MAPT pathology and neuroinflammation. However, the exact mechanistic relationship between neuroinflammation and the various brain pathologies remains unclear. Recent studies have implicated neuronal-microglial signaling through the fractalkine receptor (CX3CR1) in neuroprotection and neurodegeneration. To examine the role of CX3CL1-CX3CR1 signaling in Alzheimer's disease and non- AD tauopathies, we conducted preliminary studies to examine the effects of CX3CR1 deficiency on both Aß and MAPT pathologies. Notably, CX3CR1 deficiency resulted in a reduction in Aß pathologies in two different mouse models of AD that was associated with altered microglial activation, while conversely, CX3CR1 deficiency in the hTau mouse model of MAPT pathology resulted in enhanced microglial activation, phosphorylation and aggregation of MAPT and behavioral impairments. Additional studies in both the Aß and MAPT models suggests that IL1 signaling may contribute to the CX3CR1 dependent alterations in AD brain pathologies. The hypothesis to be examined in the current studies is that soluble CX3CL1 released from neurons signals to CX3CR1 within microglia and plays a unique role in AD phenotypes via blocking phagocytic removal of Aß by microglia and reducing phosphorylation and aggregation of MAPT within neurons via mechanisms that involve IL1. These studies will utilize state-of-the art mouse models of Aß and MAPT pathologies, as well as CXC3CR1 knockout mice and CX3CL1 knockouts and transgenic mice to examine the effects of biochemistry, gene expression, neuropathology and behavior. The Specific Aims of this proposal are to: 1. Determine the Role of CX3CL1-CX3CR1 Signaling in a Mouse Model of Aß Deposition. 2. Determine the Role of CX3CL1-CX3CR1 Signaling in a Mouse Model of MAPT Pathology. 3. Determine the Role of IL1 Signaling in CX3CR1 Dependent Alterations in AD Pathologies.