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How do synaptic connections change in demyelinating disease?

脱髓鞘疾病中突触连接如何变化？

基本信息

批准号：
10330603
负责人：
Dorothy Patricia Schafer
金额：
$ 44.98万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
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/10330603
关键词：
Ablation Address Alzheimer&apos 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

项目摘要

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.).

多萝西·谢弗。