Age-Associated Microglia/Macrophage Response Inhibits Remyelination
Abstract
Multiple Sclerosis (MS) lesions have a loss of myelin, a fatty substance that surrounds nerve fibres. The purpose of myelin is to speed communication, but it also provides nutrients to the underlying nerve fibre. Myelin is essential for the survival of the nerve fibres; when myelin is destroyed, often, the fibre dies as well. There are currently many available medications for people with MS. However, even people with MS using the most potent available drugs still have some ongoing myelin injury. As a complementary approach, promoting myelin repair--called remyelination--is likely to provide real therapeutic benefits for people with MS. Often, remyelination is inefficient for people with MS, and there are no available drugs that boost remyelination. Remyelination is also known to decline with age, which will need to be considered during remyelination drug discovery because MS is a decades-long disease. In this project, we hope to address a critical obstacle for remyelination: age-related remyelination decline. We will also test a new therapy to promote remyelination. Exciting new therapies are being tested in clinical trials to boost remyelination. However, these therapies work poorly to promote benefit when myelinating cells are subjected to a known obstacle for repair. These obstacles are found inside the MS lesion. The environment within lesions is thus thought to be the critical regulator of remyelination. We believe the best way to make the lesion environment more favourable for remyelination is to target the cells that serve as the lesions custodians: the microglia and macrophage cells. Microglia and macrophages essential function is to clear the lesion of debris. With age, these cells become less efficient in removing debris, which is partially responsible for the age-dependent decline in remyelination. However, another possible myelin repair obstacle, not yet tested, is that older microglia and macrophages hinder remyelination by making age-related remyelination obstacles. This project aims to define the attributes of microglia and macrophages in younger and older mice using a validated remyelination model. We will also study a new potential obstacle for remyelination, the enhanced production of reactive oxygen species (ROS). Our goal is to define microglia and macrophages attributes during remyelination and determine how they are affected by aging. Our preliminary work demonstrates that microglia and macrophage are enriched for the age-related molecules called ROS. We will induce myelin injury, known as demyelination, in these mice and use deep phenotyping to understand the attributes of microglia and macrophages in younger and middle-aged mice. We choose middle-aged mice because this is the time when remyelination declines, but this age also is a vital point where many people transition into progressive MS. To define the microglia and macrophage attributes, we will use a cutting-edge technology that measures all of the RNA in each cell. Measuring RNA allows you to see what protein tools a cell is making, which gives insight into the functions it could be performing. Using this tool, we can understand on a cell-by-cell basis how microglia and macrophage participate in remyelination. We will also be able to see whether these microglia or macrophage are producing ROS molecules during remyelination in young and middle-aged mice. Finally, we will also test a drug that blocks one critical ROS producing molecules for microglia and macrophages to see if this drug improves remyelination. Boosting remyelination has the potential to provide benefits for people who have relapsing-remitting or progressive MS. People with better remyelination tend to have less disability. Here we will define how ROS relates to age-associated remyelination decline, which will uncover many new targets for MS and repair research. We will also test one drug that could one day be used to treat people with MS and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110797
Entities
People
- Jason R Plemel
Organizations
- United States Army
- University of Alberta