Acute axonal damage in three different murine models of multiple sclerosis: A comparative approach.
Axonal damage has been identified as a significant contributor to permanent clinical disability in multiple sclerosis. In the context of demyelinating disorders, this destructive event can be the result of inflammation, demyelination and/or the activation of innate defense cells such as microglia or monocytes. The relative contribution of each of these variables to acute axonal injury is, however, unknown. In the present study, we compared the extent of acute axonal damage in three different murine demyelination models using anti-amyloid precursor protein (APP) immunohistochemistry. T cell dependent (MOG35-55-induced experimental autoimmune encephalomyelitis (EAE)) as well as T cell independent demyelination models (cuprizone- and lysolecithin-induced demyelination) were used. APP+spheroids were present in all three experimental demyelination models. The number of APP+spheroids was highest within LPC-induced lesions. Equal amounts were found in the spinal cord of MOG35-55-EAE animals and the corpus callosum of cuprizone-intoxicated animals. Moreover, we detected increased immunoreactivity of the pre-synaptic protein vesicular glutamate transporter 1 (VGluT1) in demyelinated foci. VGluT1-staining revealed long stretched, ovoid-like axonal structures which co-localized with APP. In summary, we showed that acute axonal damage is evident under various experimental demyelination paradigms. Furthermore, disturbed axonal transport mechanisms, which are responsible for intra-axonal APP accumulation, do not only disturb APP, but also the transport of other synaptic proteins. These results indicate that, despite differences in their characteristics, all three models may serve as valid and suitable systems for investigating responsible mechanisms of axonal damage and potential protective strategies.
Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany.
Katharina Marie
KM
Höflich
Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany.
Cordian
C
Beyer
Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany.
Tim
T
Clarner
Department of Neuroanatomy, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany.
Christoph
C
Schmitz
Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany; Department of Neuroanatomy, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany.
Stella
S
Nyamoya
Department of Neuroanatomy, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany.
Markus
M
Kipp
Department of Neuroanatomy, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany. Electronic address: tanja.hochstrasser@med.uni-muenchen.de.
Tanja
T
Hochstrasser
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D003337:Corpus Callosum / Q000473:pathology; D003471:Cuprizone / Q000378:metabolism / Q000494:pharmacology; D003711:Demyelinating Diseases / Q000503:physiopathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D023421:Models, Animal; D009103:Multiple Sclerosis / Q000503:physiopathology*; D009186:Myelin Sheath / Q000473:pathology; D009410:Nerve Degeneration / Q000503:physiopathology*; D013116:Spinal Cord / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; C078201:Aplp1 protein, mouse; D003471:Cuprizone
APP; Axonal damage; Cuprizone; Experimental autoimmune encephalomyelitis; Lysolecithin