Mechanisms underlying mutant astrocyte-mediated demyelination in Alexander disease

Abstract

Alexander disease (AxD), a rare neurodegenerative disease, is caused by the mutation of GFAP gene whose expression is enriched in astrocytes. Thus, AxD is “a primary astrocyte disease”. AxD patients mainly show severe neurological symptoms such as psychomotor developmental delay, motor deficits etc. and white matter degeneration in their brains. However, molecular pathogenesis that leads from mutant astrocytes to white matter degeneration remains largely unclear, although AxD astrocytes are thought to gain neurotoxicity. Here, we examined the structural changes in the corpus callosum (CC) of AxD model mice carrying human mutant GFAP (Tanaka et al., GLIA, 2007). We revealed followings. (1) Immunohistochemical data showed that demyelination occurred in the CC of AxD. (2) AxD astrocytes enhanced “astrocyte reactivity” and mainly occupied demyelinated areas, suggesting that AxD astrocytes should contribute to local demyelination. (3) AxD astrocytes highly expressed Galectin-3 and Lipocalin-2, both of which are thought to control astrocytic phagocytosis. (4) Electron microscopic analysis showed that AxD astrocytes engulfed myelin, but not WT. Together, all these findings suggest that AxD astrocytes may phagocytose myelin by acquiring their abnormal phagocytic ability, thereby leading to white matter degeneration.