The role of fractalkine signaling in neurodegenerative disease

fractalkine 信号在神经退行性疾病中的作用

• 批准号: 8821678
• 负责人: Bruce T Lamb
• 金额: $ 34.34万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821678
• 关键词: Age related macular degeneration; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Animals; Anti-Inflammatory Agents; Astrocytes; Behavior; Binding; Biochemistry; Brain; Brain Pathology; CX3CL1 gene; Cause of Death; Cell Adhesion Molecules; Cessation of life; Characteristics; Communication; Dementia; Deposition; Development; Diagnosis; Disease; Disease Progression; Elderly; Epidemiologic Studies; Excision; Fractalkine; Gene Expression; Goals; Health; Human; Inflammation; Inflammatory; Interleukin-1; Knock-out; Knockout Mice; Membrane; Metabolism; Microglia; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Parkinson Disease; Partner in relationship; Pathogenesis; Pathology; Pathway interactions; Peptides; Phagocytosis; Pharmaceutical Preparations; Phosphorylation; Play; Process; Role; Senile Plaques; Signal Transduction; Staging; Stroke; Tauopathies; Testing; Transgenic Mice; Transgenic Organisms; United States; age related; amyloid precursor protein processing; anakinra; behavioral impairment; chemokine; cytokine; disability; disease phenotype; extracellular; genetic variant; hTau Mice; human CX3CR1 protein; migration; mouse model; neuroinflammation; neuron loss; neuropathology; neuroprotection; new therapeutic target; painful neuropathy; receptor; tau Proteins; tau aggregation; tau phosphorylation; therapy development

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.

描述(申请人提供)：阿尔茨海默病(AD)是老年人痴呆症最常见的原因，现在是美国第七大主要死亡原因。AD的特点和诊断是以独特的神经病理改变为特征，包括细胞外淀粉样多肽(Aü)沉积，神经元中微管相关蛋白tau(MAPT)的细胞内聚集，以及明显的神经炎症。同样，在非阿尔茨海默病中，既有丰富的MAPT病理，也有神经炎症。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(CX3CR1)传递的神经元-小胶质细胞信号与神经保护和神经退行性变有关。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，以检测CX3CR1缺乏对Aü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缺乏导致与小胶质细胞激活改变相关的Aü病理改变，而相反，在MAPT病理的hTau小鼠模型中，CX3CR1缺乏导致小胶质细胞激活、MAPT的磷酸化和聚集增强以及行为障碍。在Aü和MAPT模型中的其他研究表明，IL1信号可能在AD脑病理中CX3CR1依赖的改变中起作用。目前的研究假设是，神经元释放的可溶性CX3CL1向小胶质细胞内的CX3CR1传递信号，并通过阻断小胶质细胞吞噬细胞对A？的吞噬作用，通过参与IL1的机制减少MAPT在神经元内的磷酸化和聚集，在AD表型中发挥独特的作用。这些研究将利用最先进的Aü和MAPT病理小鼠模型，以及CXC3CR1基因敲除小鼠和CX3CL1基因敲除小鼠和转基因小鼠，以检查生化、基因表达、神经病理学和行为的影响。本研究的具体目的是：1.确定CX3CL1-CX3CR1信号在Aü沉积小鼠模型中的作用。2.确定CX3CL1-CX3CR1信号在小鼠MAPT病理模型中的作用。3.确定IL1信号在CX3CR1依赖的AD病理改变中的作用。