Multiple sclerosis (MS), neuromyelitis optica (NMO) and Baló’s disease (BD) are inflammatory demyelinating diseases of the central nervous system (CNS). We previously reported aquaporin-4 (AQP4) loss without perivascular deposition of complement or immunoglobulin in demyelinating diseases, suggesting that astrocytic damage could be a common denominator in heterogeneous demyelinating conditions. To investigate the relationship between astrocytopathy and demyelination, we focused on connexins (Cxs), which form gap junction channels between astrocytes and oligodendrocytes, and maintain myelination and homeostasis in the CNS. We pathologically evaluated the expression of astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 in autopsied tissue samples from MS, NMO and BD patients. In all BD samples, astrocytic Cx43 and oligodendrocytic Cx32/Cx47 expression was diminished in both demyelinated and preserved myelin layers. In the leading edge of BD lesions, Cx43 and AQP4 loss preceded Cx32/Cx47 loss. Half of the NMO and MS samples showed preferential loss of astrocytic Cx43 in actively demyelinating and chronic active lesions, where heterotypic Cx43/Cx47 astrocyte-oligodendrocyte gap junctions were lost. Cases with Cx43 loss were significantly associated with rapid disease progression (death within 2 years after onset), regardless of the disease phenotype. Pathologically, Cx43 loss was frequently accompanied by distal oligodendrogliopathy. These findings suggest that Cx43 astrocytopathy can occur in MS, BD and NMO. Furthermore, astrocytic Cx43 loss might be associated with disease aggressiveness and distal oligodendrogliopathy, not only in BD,but also MS and NMO. Early disruption of astrocytic foot processes could precede demyelination and contribute to the pathogenesis of demyelinating disorders.
All Science Journal Classification (ASJC) codes
- Neuroscience (miscellaneous)
- Immunology and Microbiology (miscellaneous)
- Clinical Neurology