How Do Synaptic Connections Change in Demyelinating Disease?

脱髓鞘疾病中突触连接如何变化？

• 批准号: 10548850
• 负责人: Dorothy Patricia Schafer
• 金额: $ 42.59万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548850
• 关键词: Ablation; Address; Alzheimer' s Disease; Animal Model; Astrocytes; Automobile Driving; Autopsy; Axotomy; Binding; Blood; Bone Marrow; Brain; Cell Death; Cells; Chimerism; Clinical; Complement; Complement 1q; Complement Receptor; Data; Demyelinating Diseases; Demyelinations; Dendritic Spines; Development; Disease; Encephalitis; Event; Experimental Autoimmune Encephalomyelitis; FDA approved; Fibrinogen; Frontotemporal Dementia; Functional disorder; Genetic; Gliosis; Goals; Immune; Impaired cognition; Infiltration; Inflammation; Inflammatory; Label; Light; Macrophage-1 Antigen; Mediating; Microglia; Modeling; Molecular; Molecular Genetics; Multiple Sclerosis; Mus; Myelin; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Optic Nerve; Optic Neuritis; Pathway interactions; Patients; Peripheral; Phagocytes; Process; Production; Proteins; Regulation; Relapsing-Remitting Multiple Sclerosis; Retinal Ganglion Cells; Risk Factors; Role; Signal Transduction; Source; Structure; Synapses; System; Testing; Therapeutic; Tissues; Visual; Visual System; Work; axonal degeneration; central nervous system demyelinating disorder; complement deficiency; experimental study; genetic variant; high resolution imaging; immune cell infiltrate; mouse model; mutant; neuroinflammation; neuroprotection; nonhuman primate; novel; preservation; prevent; receptor; retinogeniculate; synaptic pruning; visual dysfunction

Schafer, Dorothy P. Project Summary Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), which has a profound, currently intractable, neurodegenerative component--a large, unmet clinical need. In many neurodegenerative diseases, one of the earliest degenerative events is synapse dysfunction and loss. There is also synapse loss in MS, but the underlying molecular mechanism(s) remains an open question. The overall hypothesis of this proposal is that complement-dependent signaling underlies synapse loss in demyelinating disease in a subset of vulnerable neurons. This is largely based on our initial findings in the developing retinogeniculate circuit demonstrating that classical complement cascade proteins C1q and C3 localize to synapses and that phagocytic microglia engulf and eliminate synapses via the C3 receptor, complement receptor 3 (CR3). Strikingly, we have new evidence that a subset of retinogeniculate synapses are also engulfed by microglia, leading to synapse loss, in MS and in multiple MS-relevant animal models of demyelinating disease (e.g. non-human primate and mouse experimental autoimmune encephalomyelitis (EAE) models). We further identified that this synapse loss can occur early prior to demyelination, axon degeneration, or cell death, but is coincident with peripheral immune cell infiltration, reactive microgliosis, and increased levels of complement C1q and C3. However, unlike development, C3, but not C1q, is localized to synapses. Finally, inhibiting C3 specifically at retinogeniculate synapses in mouse EAE prevents microglial synapse engulfment, synapse loss, and visual dysfunction. These experiments establish C3 and microglia as key regulators of synapse loss in MS-relevant demyelinating disease and open up several new questions that we will explore: 1) What cells produce complement necessary for synapse elimination in demyelinating disease (Aim 1)? 2) Does microglial complement receptor CR3 regulate synapse loss in demyelinating disease (Aim 2)? 3) Which RGCs are most vulnerable to complement-mediated synapse elimination and later degeneration (Aim 3)? To address these questions, we will continue to use the retinogeniculate circuit. This is a highly tractable and powerful system for studying synaptic changes and it is highly relevant to MS, where inflammation of the optic nerve (i.e. optic neuritis) occurs in upwards of 50% of patients and results in prolonged, often permanent, visual dysfunction. We will now use a combination of cell-specific molecular genetics and high-resolution imaging of retinogeniculate synapses in the mouse EAE model to molecularly dissect synapse loss in inflammatory demyelinating disease. Results could uncover novel targets aimed at slowing or preventing neurodegeneration in MS, which could be broadly applicable to other neurodegenerative disease with synapse loss and neuroinflammation (Alzheimer’s disease, frontotemporal dementia, etc.).

Schafer，Dorothy P. 项目摘要 多发性硬化症（MS）是一种炎症性脱髓鞘性疾病，中枢神经系统（CNS），该疾病 具有深刻的，目前棘手的，神经退行性的成分 - 庞大的未满足的临床需求。许多人 神经退行性疾病，最早的退化事件之一是突触功能障碍和丧失。有 同样在MS中的突触丧失，但是潜在的分子机制仍然是一个空旷的问题。总体 该提议的假设是补体依赖性信号传导是突触损失的基础 在脆弱神经元的一部分中脱髓鞘疾病。这主要基于我们在 开发视网膜生成电路表明经典补体级联蛋白C1Q和C3 本地化到突触和吞噬小胶质细胞吞噬并通过C3受体消除突触， 补体受体3（CR3）。令人惊讶的是，我们有新的证据表明一部分视网膜生成突触是 也被小胶质细胞吞没，导致MS和多种MS相关的动物模型中导致突触丧失 脱髓鞘疾病（例如非人类灵长类动物和小鼠实验性自身免疫性脑脊髓炎（EAE） 模型）。我们进一步确定，这种突触损失可能发生在脱髓鞘，轴突变性之前， 或细胞死亡，但与周围免疫栓塞浸润，反应性小胶质细胞增多和水平升高是一致的 完成C1Q和C3。但是，与开发不同，C3（而不是C1Q）本地化为突触。最后， 在小鼠EAE中专门抑制C3的C3可防止小胶质的突触吞噬， 突触丧失和视觉功能障碍。这些实验将C3和小胶质细胞作为关键调节剂 与MS相关的脱髓鞘疾病的突触丧失，并打开了我们将要探索的几个新问题：1） 哪些细胞在脱髓鞘疾病中消除突触所必需的完成（AIM 1）？ 2）做 小胶质补体受体CR3调节脱髓鞘疾病的突触丧失（AIM 2）？ 3）RGCS 最容易受到补体介导的突触消除和后来的变性（AIM 3）？解决 这些问题，我们将继续使用视网膜生成电路。这是一个高度易加的和强大的 研究合成变化的系统，它与MS高度相关，其中视神经的炎症（即 视神经神经症）发生在50％以上的患者中，导致长时间，常见的视觉功能障碍。 现在，我们将结合细胞特异性分子遗传学和视网膜生成的高分辨率成像 小鼠EAE模型中的突触以分子剖析炎症性脱髓鞘疾病的突触丧失。 结果可能会发现旨在减慢或预防MS神经变性的新型目标，这可能是 广泛适用于其他神经退行性疾病，具有突触丧失和神经炎症（阿尔茨海默氏症） 疾病，额颞痴呆等）。