Astrocyte‐associated axonal damage in pre‐onset stages of experimental autoimmune encephalomyelitis

Abstract

Recent studies of axon-glia and glia-glia communication have emphasized interactivity and interdependence between central nervous system (CNS) components. Concurrently, data from imaging, biochemical, and morphological studies have changed the view of multiple sclerosis (MS) from a neuroinflammatory condition with primary demyelination to one in which cumulative axonal damage drives progression. We therefore studied axonal damage in the context of inflammation and glial responses, from the pre-clinical to onset stage of murine experimental autoimmune encephalomyelitis (EAE), an established MS model. We report three major findings: (1) the first evidence of axonal injury before significant T-cell entry into the parenchyma, (3) coincidence of the earliest manifestation of axonal damage and astrocytic responses, and (3) an association between accumulation of axonal and astrocytic changes and specific forms of MS. These data demonstrate the relationship between the initiation of axonal injury and early inflammation. Significantly, we show that, in common with a growing number of neurodegenerative conditions, the pathology of murine EAE is characterized by early active contribution from astrocytes. This marks a change in the understanding of the role of astrocytes in MS pathogenesis and has important implications for the development of neuroprotective strategies.

Dihydrotestosterone as a Protective Agent in Chronic Experimental Autoimmune Encephalomyelitis

“…In the present study, we also analyzed GFAP-immunoreactive astrocytes. Astrocytes are a key component in the pathogenesis of MS and EAE models [2,48,49] . For instance, in the preclinical phase of myelin oligodendrocyte glycoprotein-induced EAE, astrocytes are activated even in the absence of infiltrating immune cells, and this correlates with axonal injury [48] .…”

Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis

“…In a rat model of MOG-EAE, axonal loss occurred early in the disease course, and correlated with the number of relapses in animals with RR disease and with permanent disability in animals with progressive or long-term RR disease (Papadopoulos et al, 2006). Studies examining early axonal loss in rats or mice with EAE have reported either no correlation with inflammation or axonal damage concurrent with the appearance of small numbers of parenchymal T cells (Espejo et al, 2005;Hobom et al, 2004;Wang et al, 2005).…”

Mechanisms and Patterns of Axonal Loss in Multiple Sclerosis

“…EAE mice induced by immunization with myelin oligodendrocyte protein (MOG) peptide 35-55 show axonal vacuolization and fragmentation, as well as brain atrophy (Bannerman et al, 2005;Wang et al, 2005;Bannerman and Hahn, 2007;HerreroHerranz et al, 2008;Jones et al, 2008). C57BL/6 mice immunized with MOG in CFA exhibit intra-axonal accumulations of APP and hyperphosphorylated heavy chains (NF-H).…”