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: 10210166
• 负责人: Dorothy Patricia Schafer
• 金额: $ 47.82万
• 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/10210166
• 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; 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; Tissues; Visual; Visual system structure; Work; axonal degeneration; base; central nervous system demyelinating disorder; experimental study; genetic variant; high resolution imaging; mouse model; mutant; neuroinflammation; neuroprotection; nonhuman primate; novel; novel therapeutics; 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.).

谢弗，多萝西·P. 项目概要 多发性硬化症（MS）是一种中枢神经系统（CNS）炎症性脱髓鞘疾病， 具有深远的、目前难以解决的神经退行性成分——巨大的、未满足的临床需求。在许多 神经退行性疾病中，最早的退行性事件之一是突触功能障碍和丧失。有 多发性硬化症中也存在突触丢失，但潜在的分子机制仍然是一个悬而未决的问题。整体 该提议的假设是补体依赖性信号传导是突触损失的基础 脆弱神经元子集中的脱髓鞘疾病。这主要是基于我们的初步发现 开发视网膜原化电路，证明经典补体级联蛋白 C1q 和 C3 定位于突触，吞噬细胞小胶质细胞通过 C3 受体吞噬并消除突触， 补体受体 3 (CR3)。引人注目的是，我们有新的证据表明视网膜原突触的一个子集是 在多发性硬化症和多种与多发性硬化症相关的动物模型中，也被小胶质细胞吞噬，导致突触丢失 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）。我们进一步发现，这种突触丢失可能发生在脱髓鞘、轴突变性、 或细胞死亡，但与外周免疫细胞浸润、反应性小胶质细胞增生和水平升高同时发生 补体 C1q 和 C3。然而，与发育不同的是，C3（而不是 C1q）定位于突触。最后， 特异性抑制小鼠 EAE 视网膜原形成突触处的 C3 可防止小胶质细胞突触吞噬， 突触丧失和视觉功能障碍。这些实验将 C3 和小胶质细胞确定为关键调节因子 多发性硬化症相关脱髓鞘疾病中的突触丢失并提出了我们将探讨的几个新问题：1) 哪些细胞产生脱髓鞘疾病中突触消除所需的补体（目标 1）？ 2) 是否 小胶质细胞补体受体 CR3 调节脱髓鞘疾病中的突触损失（目标 2）？ 3) 哪些 RGC 最容易受到补体介导的突触消除和随后的退化（目标 3）？致地址 这些问题，我们将继续使用retinogeniculate电路。这是一个非常容易处理且功能强大的 研究突触变化的系统，它与多发性硬化症高度相关，其中视神经炎症（即视神经炎症） 超过 50% 的患者会发生视神经炎，并导致长期（通常是永久性）视觉功能障碍。 我们现在将结合使用细胞特异性分子遗传学和视网膜色素的高分辨率成像 小鼠 EAE 模型中的突触，从分子角度剖析炎症性脱髓鞘疾病中的突触损失。 结果可能会发现旨在减缓或预防多发性硬化症神经变性的新靶标，这可能是 广泛适用于其他具有突触丧失和神经炎症的神经退行性疾病（阿尔茨海默病） 病、额颞叶痴呆等）。