ABSTRACT
Oligodendrocyte damage is a central event in the pathogenesis of the common neuroinflammatory condition, multiple sclerosis (MS). Where and how oligodendrocyte damage is initiated in MS is not completely understood. Here, we use a combination of light and electron microscopy techniques to provide a dynamic and highly resolved view of oligodendrocyte damage in neuroinflammatory lesions. We show that both in MS and in its animal model structural damage is initiated at the myelin sheaths and only later spreads to the oligodendrocyte cell body. Early myelin damage itself is characterized by the formation of local myelin out-foldings-'myelinosomes'-, which are surrounded by phagocyte processes and promoted in their formation by anti-myelin antibodies and complement. The presence of myelinosomes in actively demyelinating MS lesions suggests that oligodendrocyte damage follows a similar pattern in the human disease, where targeting demyelination by therapeutic interventions remains a major open challenge.
Subject(s)
Multiple Sclerosis/pathology , Myelin Sheath/pathology , Oligodendroglia/pathology , Animals , Antibodies/metabolism , Complement System Proteins/metabolism , Demyelinating Diseases/pathology , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/pathology , Humans , Imaging, Three-Dimensional , Macrophages/metabolism , Mice, Inbred C57BL , Myelin Sheath/ultrastructure , Oligodendroglia/ultrastructure , Opsonin Proteins/metabolism , Organelles/metabolism , Organelles/ultrastructureABSTRACT
The correlation of light and electron microscopy of complex tissues remains a major challenge. Here we report near-infrared branding (NIRB), which facilitates such correlation by using a pulsed, near-infrared laser to create defined fiducial marks in three dimensions in fixed tissue. As these marks are fluorescent and can be photo-oxidized to generate electron contrast, they can guide re-identification of previously imaged structures as small as dendritic spines by electron microscopy.
