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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' 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

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.

项目总结 许多与年龄相关的神经退行性疾病--包括阿尔茨海默病(AD)--与 错误折叠的蛋白质沉积会促进炎症反应、神经元功能障碍和认知障碍。 我们最近发现，衰老和AD都表现出脑膜淋巴功能受损，这 最终导致颈深部淋巴结的脑脊液引流受损，以及脑脊液向颈深部淋巴结的灌流。 脑实质，共同促进废物堆积和A诱导的AD小鼠的病理。我们的预赛 数据表明，衰老也与产生干扰素γ的CD4T细胞和CD8T细胞的积累有关 在硬脑膜中，与脑膜淋巴管密切相关。干扰素γ信号代表一种 衰老脑膜淋巴管的转录特征和幼鼠脑膜淋巴管轴的增强减弱 脑脊液的功能性引流。因此，我们假设在衰老和AD期间，表达上调的 脑膜CD4T细胞和CD8T细胞分泌的干扰素γ通过直接信号转导途径损害脑膜淋巴功能 他们的干扰素γ受体，导致脑膜淋巴恶化。这种恶化后来会导致 脑脊液(CSF)脑灌注，随后导致碎片堆积和恶化 AD的进展。我们进一步假设，使用细胞因子中和抗体，我们可以保存 老年小鼠脑膜淋巴管及预防或减轻增龄相关脑功能障碍和增强 AD患者现有的免疫治疗策略。解决我们对这一提议的假设将有助于 年龄相关性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。