Periodic Reporting for period 1 - NETWORK (The biology of myelin and lipoproteins within a glial network)
Reporting period: 2022-01-01 to 2023-06-30
o What is the problem/issue being addressed?
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
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
To facilitate the rapid transmission of nerve signals, axons are surrounded by myelin, a protective, multi-layered membrane created by oligodendrocytes. The majority of myelin formation occurs early in development, leading to the creation of durable and stable membrane structures. In this study, we investigated the structural and dynamic alterations that occur in the myelin of the central nervous system during development. To do this, we conducted a detailed analysis of mouse optic nerves using advanced imaging techniques such as serial block face scanning electron microscopy (SBF-SEM) and time-lapse confocal imaging in the zebrafish spinal cord. Our research revealed that myelin undergoes significant structural changes during the early postnatal development period. Microglia engulfed and consumed myelin degeneration profiles, which exposed phosphatidylserine, acting as an "eat me" signal. In contrast, the retraction of entire myelin sheaths happened independently of microglia and involved the oligodendrocytes themselves taking up the myelin. These findings demonstrate that the initial generation of myelin during development is an imperfect process marked by abnormal structural characteristics that necessitate substantial refinement.
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.
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.
The brain ranks as the second most abundant organ in terms of lipid content, trailing only behind adipose tissue, with a significant portion of these lipids residing within myelin. Recent research has underscored the growing importance of lipid metabolism in various neurological disorders, particularly the most prevalent neurodegenerative conditions. However, there is still a profound knowledge gap when it comes to how cells manage the substantial lipid burden essential for their proper functioning. Our comprehension of this aspect of biology remains limited, mainly due to the intricate nature of lipid metabolic pathways, which exhibit extensive interconnections among diverse cell types and organs. Current investigations have predominantly focused on scrutinizing lipid metabolic processes in the CNS in isolation, a methodology that falls short of delivering a comprehensive understanding of the system's intricacies. In this context, we aim to define CNS lipoproteins, not merely as vehicles for intercellular communication, but as active participants in a surveillance and delivery system that orchestrates lipid metabolism within the intricate cellular network. This project demends expertise across various domains, spanning from biochemistry to lipid biology and genetics—an expertise that my research group possesses.