Research reportAcute axonal damage in three different murine models of multiple sclerosis: A comparative approach

- Acute axonal damage is present in three different experimental demyelination models.
- Disturbed axonal transport mechanisms are not restricted to APP.
- Microglia/monocyte response correlates with acute axonal damage.

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.