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: 8128951
• 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/8128951
• 关键词: 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; Partner in relationship; Pathogenesis; Pathology; Pathway interactions; Peptides; 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; 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. 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.

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的特征和诊断是以独特的神经病理改变为特征的，包括细胞外β-淀粉样蛋白沉积(A？)肽、神经元中微管相关蛋白tau的细胞内聚集体(MAPT)和明显的神经炎症。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AD疾病中的作用，我们进行了初步研究，以检测CX3CR1缺乏对A？和MAPT病理。值得注意的是，CX3CR1缺乏导致A？在两个不同的AD小鼠模型中，CX3CR1缺乏导致小胶质细胞激活改变，而相反，在MAPT病理hTau小鼠模型中，CX3CR1缺乏导致小胶质细胞激活、MAPT磷酸化和聚集增强以及行为障碍。A和A两门课程的其他研究？MAPT模型提示IL1信号可能参与了AD脑病理中CX3CR1依赖的改变。目前研究中要验证的假设是，神经元释放的可溶性CX3CL1向小胶质细胞内的CX3CR1传递信号，并通过阻断吞噬细胞对A？通过小胶质细胞，并通过涉及IL1的机制减少MAPT在神经元内的磷酸化和聚集。这些研究将利用最先进的A？和MAPT病理，以及CXC3CR1基因敲除小鼠和CX3CL1基因敲除小鼠和转基因小鼠，以检测生化、基因表达、神经病理和行为的影响。本研究的具体目的是：1.确定CX3CL1-CX3CR1信号在A？证词。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。 公共卫生相关性：大量研究表明，改变的神经炎症，包括小胶质细胞的激活，是在AD和非AD患者中观察到的不变特征。然而，目前尚不清楚神经元和小胶质细胞之间的小胶质细胞激活和信号的改变如何导致AD和非AD疾病以及疾病进展的不同阶段的主要病理特征。目前的研究试图检验Fractalkine信号的变化是否对A2和MAPT病理的发展起着独特的作用，这些信息将在旨在阻断疾病进展不同阶段的疾病病理的治疗方法的开发中至关重要。