Aged T-cell-derived cytokines impact meningeal lymphatics and contribute to AD

老化 T 细胞衍生的细胞因子影响脑膜淋巴管并导致 AD

基本信息

批准号：
10515246
负责人：
Jonathan Kipnis
金额：
$ 58.56万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-17 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10515246
关键词：
Achievement Acute Address Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer&apos s disease therapy Amyloid Antibodies Antigen Presentation Antigens Atlases Attention Attenuated Behavior Biological Markers Blood Vessels Brain Brain Drains CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Count Cell physiology Cells Cerebrospinal Fluid Cognitive deficits Cytokine Signaling Data Deep Cervical Lymph Node Deposition Deterioration Disease Progression Drainage procedure Equilibrium Excision Genetic Polymorphism Genetic Transcription HLA-DR Antigens IFNGR1 gene Immune Immune response Immunity Immunotherapy Impaired cognition Impairment Inflammatory Inflammatory Response Interferon Type II Interferons Interleukin-17 Interleukin-4 Learning Light Link Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphatic function Lymphocyte Mediating Memory Memory impairment Meningeal Meningeal lymphatic system Meninges Microglia Mus Neuraxis Neurologic Neuronal Dysfunction Outcome Pathologic Pathology Pathway interactions Patients Perfusion Peripheral Phase Phenotype Physiological Population Role Route Senile Plaques Signal Transduction Site Source T-Lymphocyte Testing Therapeutic Therapeutic Intervention Tissues Transgenic Mice abeta deposition adaptive immune response age related age related neurodegeneration aged brain dysfunction brain parenchyma cytokine genome wide association study lymphatic drainage lymphatic dysfunction lymphatic vasculature lymphatic vessel misfolded protein mouse model nervous system disorder neurogenesis neuroinflammation neutralizing antibody new therapeutic target novel overexpression preservation prevent receptor response single-cell RNA sequencing therapeutic target wasting

项目摘要

PROJECT SUMMARY Many age-related neurodegenerative diseases—including Alzheimer's disease (AD)—are associated with misfolded protein deposition that promote inflammatory responses, neuronal dysfunction, and cognitive deficits. We have recently identified that aging and AD both display impaired meningeal lymphatic function, which ultimately results in impaired CSF drainage to deep cervical lymph nodes, as well as CSF perfusion into the brain parenchyma, collectively promoting waste build up and A-induced pathologies in AD mice. Our preliminary data demonstrate that aging is also associated with the accumulation of IFNγ-producing CD4 and CD8 T cells in the dural meninges, closely associated with the meningeal lymphatics. IFNγ signaling represents a transcriptional hallmark of aged meningeal lymphatics and augmentation of this axis in young mice attenuates their functional drainage of CSF. We therefore hypothesize that during aging and in AD, elevated expression of IFNγ from meningeal CD4 and CD8 T cells impairs meningeal lymphatic function function via direct signaling on their IFNγ receptors, leading to meningeal lymphatic deterioration. Such deterioration later results in impaired brain perfusion by cerebrospinal fluid (CSF), subsequently leading to the accumulation of debris and worsening progression of AD. We further hypothesize that using cytokine neutralizing antibodies, we can preserve meningeal lymphatics in aged mice and prevent or reduce the age-associated brain dysfunctions and augment existing immunotherapy strategies in AD patients. Addressing our hypotheses of this proposal will illuminate mechanistic pathways underlying age-related meningeal lymphatic dysfunction, and identify new promising avenues for therapeutic interventions intended to reduce AD-related pathology.

项目概要许多与年龄相关的神经退行性疾病，包括阿尔茨海默病 (AD)，都与错误折叠的蛋白质沉积会促进炎症反应、神经功能障碍和认知缺陷。我们最近发现衰老和 AD 都表现出脑膜淋巴功能受损，这最终导致脑脊液向颈深部淋巴结的引流受损，以及脑脊液向颈部的灌注受损脑实质，共同促进 AD 小鼠中废物的积累和 A 诱导的病理。数据表明，衰老还与产生 IFNγ 的 CD4 和 CD8 T 细胞的积累有关在硬脑膜中，与脑膜淋巴管密切相关的 IFNγ 信号传导代表了一种。老年脑膜淋巴管的转录特征和年轻小鼠中该轴的增强减弱因此，我们努力解决衰老过程中和 AD 患者中脑脊液的功能性引流问题。来自脑膜 CD4 和 CD8 T 细胞的 IFNγ 通过直接信号传导损害脑膜淋巴功能他们的 IFNγ 受体，导致脑膜淋巴恶化，随后导致受损。脑脊液（CSF）灌注大脑，随后导致碎片积聚并导致病情恶化我们进一步进展，使用细胞因子中和抗体，我们可以保存 AD。老年小鼠的脑膜淋巴管，预防或减少与年龄相关的脑功能障碍，并增强解决 AD 患者现有的免疫治疗策略将阐明我们的假设。年龄相关脑膜淋巴功能障碍的机制途径，并确定新的有希望的旨在减少 AD 相关病理的治疗干预途径。