The Role of Microglial Lipid Phagocytosis and Recycling in Remyelination
Abstract
Objectives and Rational: Multiple sclerosis (MS) patients develop lesions in the central nervous system (CNS) in which myelin is damaged, known as demyelination. Myelin is a membrane made of lipids, or fats, produced by oligodendrocytes that surrounds and protects axons. After a neurological injury, oligodendrocytes can regenerate myelin to repair the damage, known as remyelination. However, remyelination of MS lesions is often incomplete, leading to permanent damage. It is unknown why remyelination of MS lesions is incomplete. Thus, this proposal aims to understand the remyelination failure in MS. The immune system plays a large role in MS disease; B cells produce antibodies that bind to myelin and target it for attack by immune cells. Notably, no current animal models reflect this specific mode of demyelination, making it difficult to study MS-specific mechanisms of remyelination failure. Therefore, we developed a new model of demyelination and remyelination using these MS-specific antibodies. When the antibodies are applied to mouse brain tissue, they induce demyelination. Upon removal, the tissue remyelinates. However, if the antibody remains (simulating an MS lesion environment) there is inefficient remyelination. Microglia, the immune cells in the CNS, are important for eating myelin debris after demyelination and recycling the lipids to be reused. Of importance, oligodendrocytes use lipids to create new myelin. However, early studies suggest that MS antibodies impair microglial functions. Highlighting the importance of these cells in remyelination, if microglia are absent from a recovering tissue slice, lesion repair is also inefficient. Therefore, this proposal tests the hypothesis that myelin removal and recycling by microglia is crucial for helping in MS lesion remyelination. In our model system, inefficient remyelination is defined by the presence of abnormal myelin structures not localized to axons, and a lack of proper myelin on the axons. Understanding why these two phenomena occur is crucial for understanding the remyelination failure in MS lesions. The aims of this project are (1) to investigate how excess lipid accumulation in microglia after eating myelin affects their function during remyelination, and (2) to study the importance of recycling the lipids from the myelin that microglia removed back to oligodendrocytes to produce new myelin for lesion repair. MSRP Focus Area: This proposal addresses the Central Nervous System Regenerative Potential in Demyelinating Conditions Focus Area of the Multiple Sclerosis Research Program. We have developed an innovative, disease-specific model system of demyelination and repair that utilizes myelin-binding antibodies from MS patients. This model will be used to study microglia-oligodendrocyte interactions in order to understand why remyelination fails in MS patient lesions, and identify new biological mechanisms that can be targeted to improve remyelination. Applicability to MS Patient Care: The results from this study will provide important new information about the role of microglial lipid recycling during remyelination. We will identify new druggable targets for the recycling mechanisms that may overcome the remyelination limitations in MS lesions. Such a treatment could be available within 10 years and would greatly enhance the lives of MS patients as it would stall, if not, reverse permanent damage to the brain, ideally alleviating cognitive deficits.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310901
Entities
People
- Lisa Golden
Organizations
- United States Army
- University of Colorado Denver