Neurobiol Dis. 2008 May;30(2):162-73. doi: 10.1016/j.nbd.2008.01.001. Epub 2008 Jan 26.
Pattern of axonal injury in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis: implications for multiple sclerosis.
Abstract
Axonal
damage is a correlate for increasing disability in multiple sclerosis.
Animal models such as experimental autoimmune encephalomyelitis (EAE)
may help to develop better therapeutical neuroprotective strategies for
the human disease. Here we investigate the pattern of axonal injury in
murine myelin oligodendrocyte glycoprotein peptide 35-55 (MOG) induced
EAE. Inflammatory infiltration, axonal densities and expression of
amyloid precursor protein (APP), neurofilaments (SMI31 and 32) as well
as expression of sodium channels were quantified in lesions, the
perilesional area and normal appearing white matter (NAWM).
Quantification of T cells and macrophages revealed a significant
reduction of inflammatory infiltration at later disease stages despite
an increase of demyelinated areas and persistent clinical disability. In
lesions, axonal density was already significantly reduced early and
throughout all investigated disease stages. A significant axonal loss
was also seen in the grey matter and at later time points in the
perilesion as well as NAWM. Numbers of axons characterized by
non-phosphorylated neurofilaments and re-distribution of sodium channels
1.2 and 1.6 increased over the course of MOG-EAE whilst APP positive
axons peaked at the maximum of disease. Finally, double-labeling
experiments revealed a strong colocalization of sodium channels with
APP, neurofilaments and the axonal nodal protein Caspr, but not glial
and myelin markers in actively demyelinating lesions. In summary,
progressive axonal loss distant from lesions is mainly associated with
changes in neurofilament phosphorylation, re-distribution of sodium
channels and demyelination. This axonal loss is dissociated from acute
inflammatory infiltration and markedly correlates with clinical
impairment. Consequently, therapeutic intervention may be promising at
early stages of EAE focusing on inflammation, or later in disease
targeting degenerative mechanisms.
Aucun commentaire:
Enregistrer un commentaire