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.

项目摘要/摘要 Tau病理是阿尔茨海默病(AD)及其临床进展的核心，因此 目前的治疗努力是通过免疫治疗来减少脑组织中tau的负担。首字母 播种和沉积tau与早期炎症反应有关，在人类疾病和 阿尔茨海默病小鼠模型。免疫系统对tau和其他聚集物的积累做出快速反应 蛋白质，以便从大脑中清除它们，防止进一步的免疫激活。但是，如果净空是 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扩散和积累。Tau病理和tau病理之间的复杂关系 炎症仍然没有得到充分的描述。我们鉴定了转录因子干扰素调节因子5 (IRF5)作为病理性tau反应中小胶质细胞活化的新介质。我们发现IRF5是 病理性tau刺激后，小胶质细胞激活，即核定位，IRF5的表达 与健康献血者相比，AD患者脑组织中的含量增加。此外，缺乏IRF5的衰老小鼠 表现为可溶性tau的积累增加。综上所述，这些数据暗示了IRF5在小胶质细胞中的新作用 聚集的、病理性tau的免疫监控。这一应用的前提是IRF5介导的 小胶质细胞中的信号转导是调节tau蓄积的关键步骤。在这份提案中，我们将1)测试 假设IRF5是大脑中病理tau的免疫监控所必需的，2)决定了 IRF5的治疗抑制对P301S小鼠疾病的发生、发展和神经变性具有保护作用。 (3)确定红外线受体5参与免疫应答的机制(S)。 陶先生。这些研究的成功完成将1)确定一个新的因素--IRF5--有助于 对大脑中致病刺激的免疫监测和2)确定IRF5是否是一种可行的治疗方法 AD和tauopathy的目标。