Postnatal development of inflammation in a murine model of Niemann-Pick type C disease: immunohistochemical observations of microglia and astroglia.

Niemann-Pick type C (NPC) is a rare and fatal neurovisceral storage disorder that is currently untreatable. In most cases, NPC is caused by mutations of the NPC1 gene, which encodes a glycoprotein playing an important role in cholesterol transport. Mice lacking the NPC1 gene exhibit several pathological features of NPC patients and have been widely used to provide insights into the mechanisms of the disease. In the present study, we analyzed the postnatal development of pathological manifestations of inflammation in several brain regions of NPC1-/- mice. Brain sections from NPC1-/- and wild-type (NPC1+/+) mice were immunostained with the MAC1 antibody, which recognizes microglia, with antibodies against glial fibrillary acidic protein (GFAP), which recognize astrocytes, and with antibodies against the cytokine interleukin-1beta (IL-1beta). Numbers of MAC1 immunopositive cells were markedly increased in several brain regions of NPC1-/- mice as early as 2 weeks of age. This effect was particularly evident in globus pallidus, ventral lateral thalamus, medial geniculate nucleus, and cerebellum. MAC1-immunopositive cells had enlarged cell bodies and shorter processes, suggesting they were in an active state. By 4 weeks, most brain structures exhibited enhanced microglial activation in NPC1-/- mice, and this was maintained at 12 weeks. At 2 weeks, reactive astrocytes were only observed in the ventral lateral thalamus while they were present throughout the brain of NPC1-/- mice at 4 weeks of age. Moreover, the astroglial reaction coincided with up-regulation of the cytokine, interleukin-1beta, in most, but not all brain regions. In particular, no interleukin-1beta up-regulation was observed in regions devoid of neuronal degeneration. These results suggest that microglial activation precedes and might be causally related to neuronal degeneration, while astrocyte activation might be a consequence of neuronal degeneration.