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: 8629804
• 负责人: Bruce T Lamb
• 金额: $ 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/8629804
• 关键词: A-Microtubule; Age related macular degeneration; Alzheimer' s Disease; Amyloid; Amyotrophic Lateral Sclerosis; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; Behavior; Behavioral; 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; Inflammation; Inflammatory; Interleukin-1; Knock-out; Knockout Mice; Membrane; Metabolism; Microglia; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neuropathy; Parkinson Disease; Partner in relationship; Pathogenesis; Pathology; Pathway interactions; Phagocytosis; Pharmaceutical Preparations; Phosphorylation; Play; Process; Role; Senile Plaques; Signal Transduction; Staging; 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; peptide A; public health relevance; 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 ?-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.

描述（由申请人提供）：老年人最常见的痴呆症原因阿尔茨海默氏病（AD）现在是美国第七主要死亡原因。 AD的特征和诊断是由独特的神经病理学改变，包括 - 淀粉样蛋白（A？）肽的细胞外沉积物，微管相关蛋白TAU（MAPT）的细胞内聚集体和明显的神经炎症。同样，在非AD tauopathies中，同时也存在丰富的MAPT病理学和神经炎症。但是，神经炎症与各种脑病理之间的确切机械关系尚不清楚。最近的研究表明，神经元受体（CX3CR1）在神经保护和神经变性中都表明了神经元 - 神经信号。为了检验CX3CL1-CX3CR1信号传导在阿尔茨海默氏病和非AD tauopanties中的作用，我们进行了初步研究以检查CX3CR1缺乏对两个A的影响？和MAPT病理。值得注意的是，CX3CR1缺乏导致A减少？与小胶质细胞激活改变有关的两种不同的AD小鼠模型中的病理学，而相反，MAPT病理学HTAU小鼠模型中的CX3CR1缺乏导致小胶质细胞激活，MAPT和行为障碍的磷酸化和磷酸化和聚集。两者的其他研究？ MAPT模型表明，IL1信号传导可能有助于AD脑病理学的CX3CR1依赖性改变。目前的研究中要研究的假设是，可溶性CX3CL1从神经元信号释放到小胶质细胞中的CX3CR1，并通过阻止A的吞噬细胞去除A？通过小胶质细胞并通过涉及IL1的机制来减少神经元内MAPT的磷酸化和聚集。这些研究将利用A的最新鼠标模型？ MAPT病理以及CXC3CR1基因敲除小鼠和CX3CL1敲除和转基因小鼠，以检查生物化学，基因表达，神经病理学和行为的影响。该建议的具体目的是：1。确定CX3CL1-CX3CR1信号在A的小鼠模型中的作用？沉积。 2。确定CX3CL1-CX3CR1信号在MAPT病理的小鼠模型中的作用。 3。确定IL1信号在AD病理学中依赖性依赖性变化中的作用。