TSPO and Neuroinflammation in Alzheimer's Disease

TSPO 和阿尔茨海默氏病的神经炎症

• 批准号: 10505310
• 负责人: Tomas R Guilarte
• 金额: $ 36.88万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10505310
• 关键词: Administrative Supplement; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Animal Model; Astrocytes; Biological Markers; Brain; Cognitive deficits; Data; Dementia; Disease; Disease Progression; Disease associated microglia; Economics; Event; Family; Gene Dosage; Gene Expression; Goals; Immunohistochemistry; Individual; Knockout Mice; Laboratories; Learning; Life Cycle Stages; Measures; Methods; Microglia; Morbidity - disease rate; Mus; NADPH Oxidase; Nerve Degeneration; Neurodegenerative Disorders; Oxidative Stress; Pathology; Personal Satisfaction; Population; Production; Proteins; Public Health; Reactive Oxygen Species; Recording of previous events; Role; Senile Plaques; United States National Institutes of Health; Validation; Wild Type Mouse; Work; abeta accumulation; cognitive function; combat; molecular targeted therapies; mortality; neuroinflammation; neuron loss; novel; novel therapeutic intervention; parent grant; sex; social; therapeutic development

Administrative Supplement Summary/Abstract: Alzheimer's disease (AD) is the most common form of dementia and one of the leading causes of morbidity and mortality worldwide. AD has a profound economic and social burden impacting the well-being of individuals, families, and a significant percentage of the world's population. It is one of the most pressing problems facing public health today. Thus, there is urgency to understand disease mechanisms to develop novel therapeutic strategies to combat this devastating disease. Neuroinflammation in the form of microglia activation and oxidative stress are hallmark features of AD. Our laboratory has had a long-standing history in the validation and application of Translocator Protein 18 kDa (TSPO) as a biomarker of neuroinflammation. TSPO is expressed in microglia and our work (in the parent grant) is focused in understanding the function(s) of TSPO in microglia. We have discovered an association between TSPO and NADPH Oxidase (NOX2) in microglia suggesting that TSPO may modulate NOX2 subunit(s) gene expression altering reactive oxygen species (ROS) production and oxidative stress in the brain. TSPO levels and NOX2 activity are both significantly increased in the brains of AD subjects and in animal models of AD. Since they are both highly expressed in AD-associated microglia, their interaction may be important in ROS production and oxidative stress leading to the aggregation of β-amyloid, neuronal loss, and cognitive deficits. We hypothesize that disruption of the TSPO-NOX2 interaction in microglia may arrest AD progression. Our working hypothesis is that 5XFAD mice (animal model of AD) that are deficient in TSPO will have a lower level of AD pathology and cognitive function deficits when compared to sex- and age-matched 5XFAD mice that are wildtype for TSPO. To this goal, in specific aim 1, we propose to use 5XFAD mice and our global TSPO knockout mice to generate 5XFAD mice with different levels of TSPO gene expression. We propose to generate 5XFAD mice that are wiltype, heterozygous, and deficient for TSPO. The goal of specific aim 2 is to use these mice to obtain preliminary data on the impact of TSPO gene dosage on the cognitive function deficits and hallmark AD pathology in 5XFAD mice. We will use the Barnes maze (spatial learning task) as one measure of cognitive function and will assess β-amyloid plaque load, and microglia and astrocyte activation using immunohistochemistry methods. The proposed studies resulting from this administrative supplement will leverage the ongoing studies in the parent grant on the association of TSPO and NOX2 in microglia and will extend them to their potential role in the neuroinflammation and neurodegeneration associated with AD. The data generated will serve to provide preliminary evidence for a larger and more comprehensive NIH proposal on the role of TSPO and NOX2 in the initiation and progression of the hallmark pathology and cognitive deficits in AD using a life course approach.

摘要/摘要：阿尔茨海默病（AD）是阿尔茨海默病最常见的形式。 痴呆是世界范围内发病率和死亡率的主要原因之一。AD具有深刻的经济和 影响个人、家庭和世界上相当一部分人口福祉的社会负担 人口这是当今公共卫生面临的最紧迫问题之一。因此，迫切需要 了解疾病机制，以开发新的治疗策略来对抗这种毁灭性的疾病。 以小胶质细胞活化和氧化应激形式的神经炎症是AD的标志性特征。我们 实验室在验证和应用转运蛋白18 kDa方面有着悠久的历史 （TSPO）作为神经炎症的生物标志物。TSPO在小胶质细胞中表达，我们的工作（在父母资助中） 重点是了解TSPO在小胶质细胞中的功能。我们发现了一种联系 TSPO和NADPH氧化酶（NOX 2）在小胶质细胞中的表达，表明TSPO可能调节NOX 2亚基基因 表达改变活性氧（ROS）的产生和脑中的氧化应激。TSPO水平 和NOX 2活性在AD受试者的脑和AD的动物模型中均显著增加。以来 它们都在AD相关小胶质细胞中高度表达，它们的相互作用可能对活性氧的产生很重要 以及氧化应激导致β-淀粉样蛋白聚集、神经元损失和认知缺陷。我们 假设小胶质细胞中TSPO-NOX 2相互作用的破坏可以阻止AD进展。我们的工作 假设TSPO缺陷5XFAD小鼠（AD动物模型）将具有较低的AD水平 与性别和年龄匹配的野生型5XFAD小鼠相比， 对于TSPO。为此，在具体目标1中，我们提出使用5XFAD小鼠和我们的全局TSPO敲除小鼠， 以产生具有不同TSPO基因表达水平的5XFAD小鼠。我们建议产生5XFAD小鼠 野生型、杂合型和TSPO缺陷型。具体目标2的目标是使用这些小鼠获得 TSPO基因剂量对认知功能缺陷和标志性AD影响的初步数据 5XFAD小鼠的病理学。我们将使用巴恩斯迷宫（空间学习任务）作为认知能力的一种测量方法。 功能，并将评估β-淀粉样蛋白斑块负荷，以及小胶质细胞和星形胶质细胞活化， 免疫组织化学方法。根据这一行政补充文件提出的拟议研究将 利用正在进行的关于小胶质细胞中TSPO和NOX 2相关性的研究， 将它们扩展到它们在与AD相关的神经炎症和神经变性中的潜在作用。的 所产生的数据将为更大、更全面的NIH提案提供初步证据， TSPO和NOX 2在以下疾病的标志性病理学和认知缺陷的起始和进展中的作用： AD使用生命过程方法。