Cytokine Modulation of AB Associated Pathologies in Mouse Models of AD

AD 小鼠模型中 AB 相关病理的细胞因子调节

• 批准号: 8429401
• 负责人: Pritam Das
• 金额: $ 27.02万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8429401
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Amyloid deposition; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Receptors; Attenuated; Automobile Driving; Brain; Cell surface; Cells; Central Nervous System Diseases; Chronic; Cognitive deficits; Complex; Data; Deposition; Development; Disease; Event; Excision; Feedback; Generations; Homeostasis; Immune; Immune response; Immunologic Receptors; Individual; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interleukin-10; Interleukin-6; Lead; Mediating; Mediator of activation protein; Microglia; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Pathology; Pathway interactions; Peptides; Peripheral; Phenotype; Phosphorylation; Play; Process; Production; Reaction; Receptor Signaling; Role; Senile Plaques; Signal Transduction; System; TNF gene; Tetracyclines; Therapeutic; Time; Transgenic Mice; age related; amyloid precursor protein processing; base; chemokine; chemokine receptor; cytokine; design; disease phenotype; extracellular; in vivo; insight; macrophage; monocyte; mouse model; neurotoxic; neurotoxicity; novel; novel therapeutic intervention; preclinical study; protective effect; protein aggregate; public health relevance; receptor; receptor expression; relating to nervous system; research study; response; tau Proteins; tau dysfunction

DESCRIPTION (provided by applicant): Chronic inflammatory reactions in the brain, has been implicated to play a role in age-related neurodegenerative disorder's, such as Alzheimer's disease (AD). In AD, glial cells in the brain are alerted by the innate immune receptors on the glial cell surface following A¿ deposition, resulting in activation, phenotypic transformation and release of soluble inflammatory mediators by the glial cells. Some of these inflammatory mediators can be directly toxic to neurons and therefore they have been accused in driving neurodegeneration. Furthermore, in the case of AD, it is hypothesized that these inflammatory cytokines can potentially alter APP processing and A¿ clearance mechanisms, creating "feedback loops", that promote further A¿ accumulation. However, we have now generated a wealth of data suggesting that over-expression of inflammatory cytokines (e.g., IL-6, IFN3 and TNF1) does not significantly alter APP levels, APP processing or steady state A¿ generation in vivo. Rather, all three inflammatory cytokines have a beneficial effect, i.e., they significantly "attenuate" amyloid deposition when expressed early in the disease process and have no effect (neither increase nor decrease) on amyloid deposition when expressed in older mice with significant pre-existing amyloid burdens. In contrast, AAV mediated over-expression of anti-inflammatory cytokine IL-10 led to significantly increased amyloid deposition and exacerbated cognitive deficits in APP transgenic mice (details in Specific Aim 2). Thus, depending on the timing and context, the actions of individual cytokines may produce divergent and unexpected effects during the disease process. Growing evidence now suggests that neural- immune interactions in the brain are intricately connected, complex and engage in significant crosstalk to maintain brain homeostasis and protect the brain. In AD, the role of these complex neural-glial interactions and immune responses in the brain are largely unresolved. In this proposal, we will take advantage of our AAV system to explore the effects of individual cytokines and chemokines particularly as it relates to AD-associated pathologies. The studies outlined in this proposal will provide insight into how specific neuro-inflammatory and neuro-modulatory reactions affect amyloid deposition and microtubule -associated protein tau pathology, the two hallmark pathological features of AD.

描述（由申请人提供）：大脑中的慢性炎症反应，已被认为在与年龄相关的神经退行性疾病（如阿尔茨海默病（AD））中发挥作用。在阿尔茨海默病中，脑内的神经胶质细胞在A¿沉积后被神经胶质细胞表面的先天免疫受体警告，导致神经胶质细胞激活、表型转化和释放可溶性炎症介质。这些炎症介质中的一些可以直接对神经元有毒，因此它们被指控在驱动神经变性。此外，在AD的情况下，假设这些炎症细胞因子可以潜在地改变APP处理和A¿清除机制，形成“反馈循环”，促进A¿的进一步积累。然而，我们现在获得的大量数据表明，炎症细胞因子（如IL-6、IFN3和TNF1）的过度表达不会显著改变体内APP水平、APP加工或稳态a¿生成。相反，这三种炎症细胞因子都有有益的作用，即，在疾病早期表达时，它们显著“减弱”淀粉样蛋白沉积，而在具有明显淀粉样蛋白负担的老年小鼠中表达时，它们对淀粉样蛋白沉积没有影响（既不增加也不减少）。相反，AAV介导的抗炎细胞因子IL-10过表达导致APP转基因小鼠淀粉样蛋白沉积显著增加，认知缺陷加重（详见Specific Aim 2）。因此，取决于时间和环境，个体细胞因子的作用可能在疾病过程中产生不同的和意想不到的效果。越来越多的证据表明，大脑中的神经-免疫相互作用是错综复杂的，复杂的，并参与重要的串扰，以维持大脑的内稳态和保护大脑。在阿尔茨海默病中，这些复杂的神经胶质相互作用和大脑免疫反应的作用在很大程度上尚未解决。在本提案中，我们将利用我们的AAV系统来探索个体细胞因子和趋化因子的作用，特别是因为它与ad相关的病理有关。本提案中概述的研究将深入了解特异性神经炎症和神经调节反应如何影响淀粉样蛋白沉积和微管相关蛋白tau病理，这是AD的两个标志性病理特征。