The role of fractalkine signaling in neurodegenerative disease

描述（由申请人提供）：阿尔茨海默病（AD）是老年痴呆症的最常见原因，目前是美国第七大死亡原因。AD的特征和诊断是独特的神经病理学改变，包括细胞外沉积的？淀粉样蛋白（A？）肽，神经元中微管相关蛋白tau（MAPT）的细胞内聚集体和显著的神经炎症。类似地，在非AD tau蛋白病中，存在丰富的MAPT病理学和神经炎症。然而，神经炎症和各种脑病理之间的确切机制关系仍不清楚。最近的研究表明，通过Fractalkine受体（CX 3CR 1）的神经元-小胶质细胞信号传导参与神经保护和神经退行性变。为了研究CX 3CL 1-CX 3CR 1信号在阿尔茨海默病和非AD tau蛋白病中的作用，我们进行了初步研究，以研究CX 3CR 1缺乏对A？和MAPT病理学。值得注意的是，CX 3CR 1缺陷导致A？在两种不同的AD小鼠模型中，CX 3CR 1缺乏导致与改变的小胶质细胞活化相关的AD病理学，而相反地，在MAPT病理学的hTau小鼠模型中，CX 3CR 1缺乏导致增强的小胶质细胞活化、磷酸化和MAPT聚集以及行为障碍。在这两个A？MAPT模型提示IL 1信号转导可能参与AD脑病理中的CX 3CR 1依赖性改变。在目前的研究中要检查的假设是，从神经元释放的可溶性CX 3CL 1信号CX 3CR 1内的小胶质细胞，并发挥独特的作用，在AD表型通过阻断吞噬细胞清除A？通过小胶质细胞和减少磷酸化和聚集的MAPT神经元内的机制，涉及IL 1。这些研究将利用国家的最先进的小鼠模型A？和MAPT病理学，以及CXC 3CR 1敲除小鼠和CX 3CL 1敲除小鼠和转基因小鼠，以检查生物化学、基因表达、神经病理学和行为的影响。本提案的具体目标是：1.确定CX 3CL 1-CX 3CR 1信号转导在A？小鼠模型中的作用作证。 2.确定CX 3CL 1-CX 3CR 1信号传导在MAPT病理学小鼠模型中的作用。 3.确定IL 1信号转导在AD病理学中CX 3CR 1依赖性改变中的作用。 公共卫生相关性：许多研究已经证明，改变的神经炎症，包括小胶质细胞活化是在AD和非AD tau蛋白病中观察到的不变特征。然而，目前尚不清楚改变的小胶质细胞活化和神经元和小胶质细胞之间的信号传导如何有助于AD和非AD tau蛋白病的主要病理标志以及疾病进展的不同阶段。目前的研究试图检查fractalkine信号传导的改变是否对A2和MAPT病理的发展有独特的贡献，这些信息对于开发旨在阻断疾病进展不同阶段的疾病病理的疗法至关重要。

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 ?-amyloid (A?) 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 A? and MAPT pathologies. Notably, CX3CR1 deficiency resulted in a reduction in A? 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 A? 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 A? 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 A? 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 A? 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. PUBLIC HEALTH RELEVANCE: Numerous studies have demonstrated that altered neuroinflammation, including microglial activation is an invariant feature observed in AD and non-AD tauopathies. However, it remains unclear how altered microglial activation and signaling between neurons and microglia contributes to the primary pathological hallmarks of AD and non-AD tauopathies and at different stages of disease progression. The current studies seek to examine whether alterations in fractalkine signaling contributes uniquely to the development of A2 and MAPT pathologies, information that will be critical in the development of therapies aimed at blocking disease pathologies at different stages of disease progression.