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Demyelination and axonal damage in a non-human primate model of multiple sclerosis
G Mancardi1, B Hart, L Roccatagliata
1Department of Neurological Sciences and Vision, University of Genoa, Via De Toni 5, 16132 Genoa, Italy. neurolab@cisi.unige.it
Abstract:
The demyelinating plaque is the paradigmatic lesion of multiple sclerosis (MS), but only recently attention has been given to axonal damage and to its role in the pathophysiology of disease. Albeit the possible relevance of axonal loss in MS and its experimental models, the amount and timing of axonal sufferance has been addressed only in experimental autoimmune encephalomyelitis (EAE) of rodents. In this report we observed that, in the marmoset model of EAE, axonal damage occurs early during the demyelinating process as assessed by immunoreactivity for amyloid precursor protein (APP) and non-phosphorylated neurofilaments (SMI-32 positive) detected mostly in early active lesions compared to late active and normal appearing white matter. The rare occurrence of morphological features of axonal transection, such as APP or SMI-32 positive spheroids and swellings, as well as an increase of neurofilament density in the demyelinated axons without accumulation of electron dense organelles or osmiophilic bodies, at electron microscopy, suggests that early axonal damage may be, at least in part, a reversible process. These findings are of relevance for the development of therapies, which can protect axons and enhance their function and survival.
Insights
Early axonal damage in multiple sclerosis (MS) models may be reversible. This study in marmosets reveals early axonal damage during demyelination, suggesting potential for therapeutic intervention.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Demyelinating plaques are key in multiple sclerosis (MS), but axonal damage is increasingly recognized in its pathophysiology.
- Previous studies on axonal damage timing and extent were limited to rodent models of experimental autoimmune encephalomyelitis (EAE).
Purpose of the Study:
- To investigate the timing and nature of axonal damage in the marmoset model of EAE.
- To assess the potential reversibility of early axonal damage in this MS model.
Main Methods:
- Utilized marmoset model of EAE.
- Assessed axonal damage via immunoreactivity for amyloid precursor protein (APP) and non-phosphorylated neurofilaments (SMI-32).
- Examined lesions (early active, late active, normal-appearing white matter) using light and electron microscopy.
Main Results:
- Axonal damage, indicated by APP and SMI-32 positivity, was detected early in the demyelinating process, primarily in active lesions.
- Morphological signs of axonal transection (spheroids, swellings) were rare.
- Electron microscopy showed increased neurofilament density without significant organelle accumulation, suggesting partial reversibility.
Conclusions:
- Early axonal damage in the marmoset EAE model occurs during demyelination and may be partially reversible.
- These findings are crucial for developing therapies aimed at protecting and enhancing axonal function and survival in MS.