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

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' 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

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.

项目总结/摘要 Tau病理学对于阿尔茨海默病（AD）的发展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脑中的tau负荷。初始 tau的播种和沉积与早期炎症反应有关，在人类疾病和 AD小鼠模型。免疫系统对tau蛋白和其他聚集蛋白的积累迅速作出反应。 蛋白质，以清除它们从大脑和防止进一步的免疫激活。但是，如果清除是 如果不成功，聚集的蛋白质的积累可能会导致过度炎症， 矛盾的是，更多的tau蛋白扩散和积累。tau蛋白病理学和 炎症仍然没有完全特征化。我们鉴定了转录因子干扰素调节因子5 （IRF 5）作为响应于病理性tau的小胶质细胞活化的新介质。我们发现IRF 5是 在用病理性tau刺激后，IRF 5在小胶质细胞中被激活，即核定位，并且IRF 5的表达被激活。 与健康供体相比，AD患者的脑组织中的蛋白质含量增加。此外，缺乏IRF 5的老年小鼠 显示可溶性tau的积累增加。总之，这些数据表明IRF 5在小胶质细胞中的新作用 聚集的病理性tau的免疫监视。本申请的前提是IRF 5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IRF 5是脑中病理性tau蛋白的免疫监视所必需的，2）确定是否 IRF 5的治疗性抑制保护P301 S小鼠免于疾病发作、进展和神经变性， 和3）确定IRF 5参与针对病理性免疫应答的机制。 τ的这些研究的成功完成将1）确定一个新的因素-IRF 5-有助于 脑中致病性刺激的免疫监视和2）确定IRF 5是否是可行的治疗剂 AD和Tau蛋白病的靶点。