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（MSA）是一种致命的、进行性神经退行性疾病，其特征在于： 由于神经胶质细胞中α-突触核蛋白（α-syn）的积累，导致胼胝体和壳核中的脱髓鞘 少突胶质细胞内的细胞质内含物（GCI）。以前的数据表明，在死后MSA中， 脑，α-syn病理伴有MHCII表达和外周T细胞浸润增加 (CD4+).从CD 4 + T细胞释放的IFNγ通过结合其受体（IFNγR1）增强炎症， 通过JAK/STAT途径，激活MHCII抗原呈递。其他研究表明， 在MSA患者死后组织中发现的神经炎症可以通过修改的 AAV，Olig 001-SYN，其对少突胶质细胞具有高向性（>95%）。此外，Oligo 001-SYN啮齿动物 MSA模型显示出由于少突胶质细胞α-syn表达而引起的类似的稳健的CD 4 + T细胞应答。我 初步结果显示，通过IFN γ和MHCII表达的增加， 在Olig 001小鼠模型中。此外，当IFN γ被敲低时， 总体MHCII表达和一般神经炎症和脱髓鞘。需要IFN γ 在神经炎症和脱髓鞘中，IFN γ的细胞特异性仍然不清楚。因此， 从这个提议可以解决MSA病理学是否需要Th 1细胞（产生IFN γ的CD 4 + T细胞）。