A Mouse Model of Inflammation in Alzheimer's Disease

阿尔茨海默病炎症小鼠模型

基本信息

批准号：
7920832
负责人：
CAROL Anne COLTON
金额：
$ 31.66万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7920832
关键词：
A Mouse Alzheimer&apos s Disease Amyloid Anti-Inflammatory Agents Anti-inflammatory Asses Astrocytes Behavioral Brain Breeding Cell Count Cells Cerebrum Cessation of life Chronic Code Cognitive deficits Complex Data Dementia Deposition Disease Disease Progression Etiology Generations Genes Goals Hippocampus (Brain)Human Immune Immune response Immune system Inflammation Inflammatory Infusion procedures Interleukin-10 Interleukin-4 Intervention Knock-out Lead Life Life Cycle Stages Measures Memory Loss Messenger RNA Microglia Mus Mutate Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Nitric Oxide Synthase Pathogenesis Pathology Pathway interactions Phenotype Play Process Property Public Health Research Project Grants Role Signal Pathway Staging Subfamily lentivirinae Thalidomide Time Toxic effect Transgenic Mice Variant Ventricular candidate marker cell type cerebrovascular cytokine cytotoxic disease phenotype hydroxy-aluminum polymer immune activation mouse model neuron loss neuropathology neurovascular unit novel numb protein protective effect repaired response small hairpin RNA tau Proteins transcription factor

项目摘要

DESCRIPTION (provided by applicant): The overarching goal of this research project is to understand how the innate immune system in the brain participates in the generation of Alzheimer's disease. To accomplish this goal, we will use novel mouse models of AD that we have developed. These mice show AD-like pathology including (1) amyloid deposits, (2) hyperphosphorylated and aggregated native mouse tau in the somatodendritic neuronal compartment, (3) neuronal loss, 4) robust cognitive deficits and 5) neurovascular unit damage. The AD-like disease phenotype was generated by crossing mice that express mutated human APP with mice that lack a functional nitric oxide synthase 2 (NOS2) gene to produce a bigenic hAPP/NOS2-/- mouse. By reducing NO levels in mice during an immune response to those levels more equivalent in human, these mice express a full spectrum of AD-like pathology. Preliminary data from the APPSw/NOS2-/- mice that show a full spectrum of AD-like pathology demonstrate an inflammatory gene profile highly reminiscent of the immune profile in brains of humans with AD. In both bigenic mice and AD brain, a complex immune activation state is observed that includes genes that code for classical pro-inflammatory factors and genes that code for anti-inflammatory factors, repair factors (alternative activation) or down-regulatory responses (acquired deactivation). Our overarching hypothesis is that the immune state plays a causal role in the disease process in AD. We hypothesize that resident immune cells undergo complex changes in immune properties in response to A¿ that vary throughout the life cycle of the disease. We also hypothesize that these immune changes alter the levels of specific AD pathology or alter disease progression. We will study the brain's immune status by 1) identifying changes in the brain's innate immune system as a function of the level of AD pathology and of disease progression using specific candidate markers of immune activation states (classical, alternative and acquired deactivation), 2) investigating the causal role of the innate immune activation state in disease pathogenesis by using interventions that will modify activation profiles and 3) investigating the cytotoxic potential of TNFa, the most likely immune-regulated cytokine to damage neurons in AD. PUBLIC HEALTH REVELANCE: This project will examine the role of the brain's innate immune state in generating the neuropathology associated with chronic neurodegenerative diseases such as Alzheimer's disease.

描述（由申请人提供）：该研究项目的总体目标是了解大脑中的先天免疫系统如何参与阿尔茨海默病的产生。为了实现这一目标，我们将使用我们开发的新型 AD 小鼠模型。这些小鼠表现出类似 AD 的病理，包括 (1) 淀粉样蛋白沉积，(2) 体细胞树突神经室中过度磷酸化和聚集的天然小鼠 tau，(3) 神经元损失，4) 强大的认知能力缺陷和 5) 神经血管单位损伤是通过将表达突变的人类 APP 的小鼠与缺乏功能性一氧化氮合酶 2 (NOS2) 基因的小鼠杂交产生双基因 hAPP/NOS2-/- 小鼠而产生的。通过在免疫反应过程中将小鼠体内的 NO 水平降低至与人类相当的水平，这些小鼠表现出了来自 APPSw/NOS2-/- 小鼠的全谱 AD 样病理学，显示了完整的 AD 样病理学。 AD 样病理学谱表明，炎症基因谱与 AD 患者大脑中的免疫谱高度相似。在双基因小鼠和 AD 大脑中，观察到复杂的免疫激活状态，其中包括编码经典促炎因子的基因。我们的首要假设是，免疫状态在 AD 的疾病过程中发挥着因果作用。细胞的免疫特性经历复杂的变化响应 A¿我们还认为，这些免疫变化会改变特定 AD 病理的水平或改变疾病的进展，我们将通过以下方式研究大脑的免疫状态：1）识别大脑先天免疫系统的功能变化。使用免疫激活状态的特定候选标记（经典、替代和获得性失活）来评估 AD 病理水平和疾病进展，2) 通过使用修改激活谱的干预措施来研究先天免疫激活状态在疾病发病机制中的因果作用3）调查TNFa 是最有可能损害 AD 神经元的免疫调节细胞因子。公共卫生启示：该项目将研究大脑先天免疫状态在产生与阿尔茨海默病等慢性神经退行性疾病相关的神经病理学中的作用。