Periodic Reporting for period 1 - NETWORK (The biology of myelin and lipoproteins within a glial network)
Berichtszeitraum: 2022-01-01 bis 2023-06-30
Myelin, a crucial component of the nervous system, enhances nerve signal transmission and supports axons. Most myelin forms during childhood, created by specialized cells called oligodendrocytes. Myelin is long-lasting but can accumulate damage over time, leading to age-related degeneration. The myelin life cycle involves three phases: development, adult maintenance, and aging degradation. We aim to understand how glial cells, such as astrocytes and microglia, interact during these phases and how lipoproteins play a role in communication between cells. Breakdown of myelin during aging could impact glial cell function. Mouse models will help study lipoprotein responses in aging and neurodegenerative diseases.
o Why is it important for society?
The major lipoprotein of the CNS, APOE, is a risk factor for many neurodegenerative diseases such as Alzheimer’s disease. We hope that an increased understanding of lipoproteins in the CNS will contribute to the design of novel strategies in treating these diseases.
o What are the overall objectives?
The project has several major objectives: To determine intrinsic and extrinsic lipid metabolic pathways in developmental myelination and remyelination; to uncover lipid metabolic pathways associated with myelin degeneration during; to establish aging and anti-oxidative and detoxifying functions of lipoprotein in the CNS; to understand the biology of apolipoprotein defense system in age-related neurodegenerative diseases
One of the key features of aging in the nervous system is the decline in both the volume and function of white matter, yet the specific mechanisms responsible for white matter damage remain unclear. In our current investigation, we observed age-related changes in the state of oligodendrocytes, leading to a decrease in the overall density of oligodendrocytes in the aging white matter of mice. Through single-cell RNA sequencing, we identified a subgroup of oligodendrocytes that respond to interferon (IFN) and are located in close proximity to CD8+ T cells within the aging white matter. Interestingly, the absence of functional lymphocytes reduced the number of IFN-responsive oligodendrocytes and prevented oligodendrocyte loss, while inhibiting T-cell checkpoints exacerbated the aging-related response. Additionally, we discovered a subgroup of microglia that respond to IFN and are dependent on lymphocytes, residing near CD8+ T cells within the aging white matter.
In summary, our research provides evidence that CD8+ T cell-induced, IFN-responsive oligodendrocytes and microglia play crucial roles as modifiers of white matter aging.
J Cell Biol. 2023 Mar 6;222(3):e202204010. doi: 10.1083/jcb.202204010. Epub 2023 Jan 13.
Nat Neurosci. 2022 Nov;25(11):1446-1457. doi: 10.1038/s41593-022-01183-6. Epub 2022 Oct 24.