Interferon-gamma mediates neuroinflammation, demyelination, and neurodegeneration in a mouse model of multiple system atrophy (MSA)

干扰素-γ 介导多系统萎缩 (MSA) 小鼠模型中的神经炎症、脱髓鞘和神经变性

• 批准号: 10754742
• 负责人: Nicole Corbin-Stein
• 金额: $ 4万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10754742
• 关键词: Acceleration; Address; Aging; Agreement; Alzheimer' s Disease; Antigen Presentation; Antigen-Presenting Cells; Attenuated; Autopsy; Behavior; Binding; Bioinformatics; CD3 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Aging; Cells; Corpus Callosum; Corpus striatum structure; Cytoplasmic Inclusion; Data; Defect; Demyelinating Diseases; Demyelinations; Disease; Disease Progression; Dorsal; Fellowship; Flow Cytometry; Genetic; Goals; HLA Antigens; HLA-DR Antigens; Immune; Immunohistochemistry; Infiltration; Inflammation; Inflammatory; Innate Immune Response; Interferon Type II; Knock-out; Knowledge; Lateral; Lead; Lesion; Life; Macrophage; Mediating; Mentors; Microglia; Modeling; Motor; Movement Disorders; Multiple Sclerosis; Multiple System Atrophy; Mus; Myeloid Cells; Nerve Degeneration; Neurodegenerative Disorders; Oligodendroglia; Onset of illness; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Positioning Attribute; Postdoctoral Fellow; Process; Production; Research Personnel; Rodent; Rodent Model; Role; Specificity; Substantia nigra structure; T cell response; T-Lymphocyte; Th1 Cells; Tissues; Tropism; Viral Vector; Work; adaptive immune response; adeno-associated viral vector; alpha synuclein; cerebral atrophy; cytokine; immune cell infiltrate; knock-down; motor behavior; motor deficit; mouse model; neuroimmunology; neuroinflammation; neuron loss; neutralizing antibody; overexpression; prevent; putamen; receptor; response; senescence; synucleinopathy; transcription factor; transcriptome sequencing

Multiple system atrophy (MSA) is a fatal, progressive neurodegenerative disease that is characterized by demyelination in the corpus callosum and putamen due to the accumulation of alpha synuclein (α-syn) in glial cytoplasmic inclusions (GCI) within the oligodendrocytes. Previous data has shown that in post-mortem MSA brain, α-syn pathology is accompanied by MHCII expression and increased infiltration of peripheral T cells (CD4+). IFNγ released from CD4+ T cells enhances inflammation by binding to its receptor (IFNγR1) and, through the JAK/STAT pathway, activates MHCII antigen presentation. Other studies have shown, the neuroinflammation found in post-mortem tissue from MSA patients can be modeled in rodents through a modified AAV, Olig001-SYN which has a high tropism (>95%) for oligodendrocytes. Moreover, the Oligo001-SYN rodent model of MSA shows a similar robust CD4+ T cell response due to the oligodendrocyte α-syn expression. My preliminary results showed there was significant neuroinflammation via increase in IFNɣ and MHCII expression in the Olig001 mouse model. Additionally, when IFNɣ was knocked down there was a significant reduction in overall MHCII expression and general neuroinflammation and demyelination. IFNɣ is required for neuroinflammation and demyelination, however the cell specificity of IFNɣ remains unclear. Therefore, findings from this proposal can address if Th1 cells (CD4+ T cells that produce IFNɣ) are required for MSA pathology.

多系统萎缩症（MSA）是一种致命的进行性神经退行性疾病，其特征是 由于胶质细胞中 α 突触核蛋白 (α-syn) 的积累导致胼胝体和壳核脱髓鞘 先前的数据表明，在死后 MSA 中，少突胶质细胞内存在细胞质内含物 (GCI)。 大脑中，α-syn 病理学伴随着 MHCII 表达和外周 T 细胞浸润增加 (CD4+) CD4+ T 细胞释放的 IFNγ 通过与其受体 (IFNγR1) 结合来增强炎症， 其他研究表明，通过 JAK/STAT 途径激活 MHCII 抗原呈递。 MSA 患者死后组织中发现的神经炎症可以通过改良的方法在啮齿类动物中建模 AAV，Olig001-SYN，对少突胶质细胞具有高趋向性（>95%）此外，Olig001-SYN 啮齿动物。 由于少突胶质细胞 α-syn 表达，MSA 模型显示出类似的稳健 CD4+ T 细胞反应。 初步结果显示，通过 IFNɣ 和 MHCII 表达增加，存在显着的神经炎症 此外，在 Olig001 小鼠模型中，当 IFNɣ 被敲低时，IFNɣ 显着减少。 总体 MHCII 表达和一般神经炎症和脱髓鞘作用是 IFNɣ 所必需的。 神经炎症和脱髓鞘，然而 IFNɣ 的细胞特异性仍不清楚，因此，研究结果。 该提案中的内容可以解决 MSA 病理学是否需要 Th1 细胞（产生 IFNɣ 的 CD4+ T 细胞）。