Astrocyte-only Npc1 reduces neuronal cholesterol and triples life span of Npc1-/- mice.

Niemann-Pick type C (NPC) disease is an autosomal recessive, lethal neurodegenerative disorder. Although neurodegeneration of Purkinje cells in the mouse model (Npc1(-/-)) is thought to be autonomous, the basis of neuronal death in other regions of the brain remains elusive. We addressed this issue in vivo by using the glial fibrillary acidic protein (GFAP) promoter to direct astrocyte-specific, replacement expression of Npc1 in Npc1(-/-) mice. These mice showed enhanced survival, decreased neuronal storage of cholesterol associated with less accumulation of axonal spheroids, lower numbers of degenerated neurons and reactive astrocytes, and restoration of myelin tracts. Their death was not associated with the usual terminal decline in weight but instead with a loss of Purkinje cells and motor coordination. We conclude that neurodegeneration of Npc1(-/-) mice is greatly affected by the loss of fibrillary astrocyte function.