New role(s) for IRF5 as a regulator of tau accumulation in Alzheimer’s disease

IRF5 在阿尔茨海默病中调节 tau 蛋白积累的新作用

基本信息

批准号：
10302599
负责人：
Betsy J Barnes
金额：
$ 25.13万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10302599
关键词：
Acute Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid Blocking Antibodies Brain Cell Nucleus Clinical Clinical Treatment Complex Cytoplasm Data Deposition Development Disease model Fostering Gender Genotype Hippocampus (Brain)Immune Immune response Immune system Immunologic Surveillance Immunotherapy In Vitro Inflammation Inflammatory Inflammatory Response Injections Interferon Activation Interferons Kinetics Link Literature Mediating Mediator of activation protein Microglia Molecular Mus Nerve Degeneration Nuclear Onset of illness Pathogenicity Pathologic Pathology Pathway interactions Predisposition Process Prosencephalon Proteins Publishing Role Signal Transduction Stimulus Tauopathies Testing Therapeutic Time Tissues Transgenic Mice Work abeta deposition aged antibody inhibitor behavior test brain tissue cytokine genetic signature hindbrain human disease immune activation in vivo inhibitor/antagonist mouse model neuroinflammation novel pre-clinical prevent protein aggregation receptor response single-cell RNA sequencing tau Proteins tau aggregation tau interferon tau mutation therapeutic target transcription factor treatment arm

项目摘要

PROJECT SUMMARY/ABSTRACT Tau pathology is central to the development of Alzheimer’s disease (AD) and its clinical progression, hence current therapeutic efforts are directed at reducing tau burden in the brain by immunotherapy. The initial seeding and deposition of tau is associated with an early inflammatory response, in both human disease and mouse models of AD. The immune system responds rapidly to the accumulation of tau and other aggregated proteins, in order to clear them from the brain and prevent further immune activation. However, if clearance is unsuccessful, the accumulation of aggregated proteins will likely lead to excessive inflammation, and paradoxically, more tau spreading and accumulation. This complex relationship between tau pathology and inflammation is still not fully characterized. We identified the transcription factor interferon regulatory factor 5 (IRF5) as a new mediator of microglia activation in response to pathological tau. We found that IRF5 is activated, i.e. nuclear-localized, in microglia after stimulation with pathological tau, and IRF5 expression is increased in brain tissue from AD patients as compared to healthy donors. Further, aged mice lacking IRF5 showed increased accumulation of soluble tau. Together, these data suggest a new role for IRF5 in microglia immunosurveillance of aggregated, pathological tau. The premise of this application is that IRF5-mediated signaling in microglia is a critical step in regulating tau accumulation. In this proposal, we will 1) Test the hypothesis that IRF5 is required for immunosurveillance of pathological tau in the brain, 2) Determine whether therapeutic inhibition of IRF5 protects P301S mice from disease onset, progression and neurodegeneration, and 3) Determine the mechanism(s) by which IRF5 participates in the immune response against pathological tau. Successful completion of these studies will 1) identify a new factor – IRF5 – that contributes to immunosurveillance of pathogenic stimuli in the brain and 2) determine whether IRF5 is a viable therapeutic target for AD and tauopathies.

项目概要/摘要 Tau 病理学对于阿尔茨海默病 (AD) 的发生及其临床进展至关重要，因此目前的治疗努力旨在通过免疫疗法减少大脑中的 tau 蛋白负担。 tau 蛋白的播种和沉积与人类疾病和疾病的早期炎症反应有关。 AD 小鼠模型的免疫系统对 tau 蛋白和其他聚集物的积累做出快速反应。蛋白质，以便将它们从大脑中清除并防止进一步的免疫激活。如果不成功，聚集蛋白的积累可能会导致过度炎症，并且矛盾的是，更多的tau蛋白扩散和积累与tau蛋白病理学之间存在复杂的关系。我们还没有完全鉴定出炎症的转录因子干扰素调节因子5。 (IRF5) 作为小胶质细胞激活响应病理性 tau 的新介质我们发现 IRF5 是在用病理性 tau 刺激后，小胶质细胞中的 IRF5 表达被激活（即核定位）此外，与健康捐赠者相比，AD 患者的脑组织有所增加。研究显示可溶性 tau 蛋白的积累增加，这些数据表明 IRF5 在小胶质细胞中发挥着新的作用。聚集的病理性 tau 的免疫监视该应用的前提是 IRF5 介导的。小胶质细胞中的信号传导是调节 tau 积累的关键步骤，在本提案中，我们将 1) 测试。假设大脑中病理性 tau 蛋白的免疫监视需要 IRF5，2) 确定是否 IRF5 的治疗性抑制可保护 P301S 小鼠免受疾病发作、进展和神经变性， 3)确定IRF5参与针对病理性免疫反应的机制成功完成这些研究将 1) 确定一个新的因子——IRF5——它有助于对大脑中致病性刺激的免疫监视，2) 确定 IRF5 是否是一种可行的治疗方法 AD 和 tau 蛋白病的靶标。