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.

项目摘要 许多与年龄相关的神经退行性疾病-包括阿尔茨海默病（AD）-与 错误折叠的蛋白质沉积促进炎症反应、神经元功能障碍和认知缺陷。 我们最近发现，衰老和AD都显示出受损的脑膜淋巴功能， 最终导致脑脊液引流至颈深淋巴结受损，以及脑脊液灌注至 脑实质，共同促进AD小鼠中的废物积聚和AD诱导的病理。我们的初步 数据表明，衰老也与产生IFNγ的CD 4和CD 8 T细胞的积累有关， 在硬脑膜中，与脑膜炎密切相关。IFNγ信号转导代表了一种 老年脑膜炎的转录标志和年轻小鼠中该轴的增强减弱了 他们的脑脊液引流功能因此，我们假设在衰老和AD中， 来自脑膜CD 4和CD 8 T细胞的IFNγ通过直接信号传导损害脑膜淋巴功能 它们的IFNγ受体，导致脑膜淋巴恶化。这种恶化后来导致受损 脑脊液（CSF）脑灌注，随后导致碎片积聚和恶化 AD的进展。我们进一步假设，使用细胞因子中和抗体， 老年小鼠的脑膜炎，预防或减少与年龄相关的脑功能障碍， 现有的免疫治疗策略。解决我们的假设，这一建议将阐明 年龄相关的脑膜淋巴功能障碍的机制途径，并确定新的有前途的 旨在减少AD相关病理的治疗干预途径。