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.
The seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer’s disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to APOE other genes expressed in microglia related to immune, lipid, and endocytic functions. Generating a novel mouse model, along with optimizing experimental protocols for the biochemical purification of APOE, enabled us to identify fibrillary aggregates of APOE in mice with Aβ amyloidosis and in human AD brain autopsies. These APOE aggregates that stain positive for b-sheet binding dyes triggered Aβ amyloidosis within the endo-lysosomal system of microglia, in a process influenced by microglial lipid metabolism and the Janus kinase/signal transducers and activators of transcription signaling pathway. Taking these observations together, we propose a model for the onset of Aβ amyloidosis in AD, suggesting that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ plaque formation.
Kaji et al. Apolipoprotein E aggregation in microglia initiates Alzheimer's disease pathology by seeding β-amyloidosis. Immunity. 2024 Nov 12;57(11):2651-2668.e12.
