title: Abnormal morphology of myelin and axon pathology in murine models of multiple sclerosis.
abstract: Demyelination and axonal damage are responsible for neurological deficits in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. However, the pathology of axonal damage in MS is not fully understood. In this study, histological analysis of morphological changes of axonal organelles during demyelination in murine models was investigated by scanning electron microscopy (SEM) using an osmium-maceration method. In cuprizone-induced demyelination, SEM showed typical morphology of demyelination in the corpus callosum of mouse brain. In contrast, SEM displayed variations in ultrastructural abnormalities of myelin structures and axonal organelles in spinal cord white matter of experimental autoimmune encephalomyelitis (EAE) mice, an animal model of MS. Myelin detachment and excessive myelin formation were observed as typical morphological myelin abnormalities in EAE. In addition, well-developed axoplasmic reticulum-like structures and accumulated mitochondria were observed in tortuous degenerating/degenerated axons and the length of mitochondria in axons of EAE spinal cord was shorter compared with naïve spinal cord. Immunohistochemistry also revealed dysfunction of mitochondrial fusion/fission machinery in EAE spinal cord axons. Moreover, the number of Y-shaped mitochondria was significantly increased in axons of the EAE spinal cord. Axonal morphologies in myelin basic protein-deficient shiverer mice were similar to those in EAE. However, shiverer mice had "tortuous" (S-curve shaped mitochondria) and larger mitochondria compared with wild-type and EAE mice. Lastly, analysis of human MS patient autopsied brains also demonstrated abnormal myelin structures in demyelinating lesions. These results indicate that morphological abnormalities of myelin and axonal organelles play important role on the pathogenesis of axonal injury in demyelinating diseases.
authors.affiliation: Department of Functional Anatomy and Neuroscience, Asahikawa Medical University, Asahikawa 078-8510, Japan. Electronic address: ybando@asahikawa-med.ac.jp.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Bando
authors.affiliation: Department of Functional Anatomy and Neuroscience, Asahikawa Medical University, Asahikawa 078-8510, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Nomura
authors.affiliation: Department of Microscopic Anatomy and Cell Biology, Asahikawa Medical University, Asahikawa 078-8510, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Bochimoto
authors.affiliation: Department of Functional Anatomy and Neuroscience, Asahikawa Medical University, Asahikawa 078-8510, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Murakami
authors.affiliation: Department of Functional Anatomy and Neuroscience, Asahikawa Medical University, Asahikawa 078-8510, Japan.
authors.forename: Tatsuhide
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Microscopic Anatomy and Cell Biology, Asahikawa Medical University, Asahikawa 078-8510, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Functional Anatomy and Neuroscience, Asahikawa Medical University, Asahikawa 078-8510, Japan.
authors.forename: Shigetaka
authors.initials: S
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D001344:Autopsy; D001369:Axons / Q000473:pathology* / Q000648:ultrastructure; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003471:Cuprizone / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D003471:Cuprizone
keywords: Axon; Axonal injury; Demyelination; Multiple sclerosis; Myelin