Neurodegeneration in the Niemann-Pick C mouse: glial involvement.

Abstract

A mouse model of Niemann-Pick type C disease has been found that exhibits neuropathology similar to the human condition. There is an age-related neurodegeneration in several brain regions and a lack of myelin in the corpus callosum in these mice. The purpose of the present study was to examine the Niemann-Pick mouse and determine whether: (1) microglia and astrocytes exhibit ultrastructural pathology similar to that found in neurons; (2) nerve fiber number is reduced when the myelin sheath is absent; and (3) the lysosomal hydrolase, cathepsin-D, is involved in the neurodegenerative process. Using light and electron microscopic methods, and immunocytochemistry, Niemann-Pick and control animals were examined at several ages. Cathepsin-D content was semi-quantitatively measured in neurons and glial cells in brain regions known to exhibit neurodegeneration, as was the density of glial fibrillary acidic protein-labeled astrocytes. The Niemann-Pick mouse exhibited: (1) an age-related increase in inclusion bodies in microglia and astrocytes, similar to that observed within neurons; (2) an almost complete absence of myelin in the corpus callosum by 7-8 weeks of age, along with a 30% reduction in the number of corpus callosum axons; (3) a mild age-related increase in cathepsin-D content within nerve cells in many brain regions. However, the cathepsin-D elevation was greatest in microglial cells; (4) an age-related increase in the number of microglial cells containing intense cathepsin-D immunoreactivity in both the thalamus and cerebellum. Both of these brain regions have been shown previously to exhibit an age-related loss of neurons; and (5) an increase in the number of reactive astrocytes immunostained for glial fibrillary acidic protein, especially in the thalamus and cerebellum. These data indicate that glial cells are a major target for pathology in the Niemann-Pick mouse. The lack of myelin within the corpus callosum may be related to the loss of nerve fibers in this structure. The increase in cathepsin-D-laden microglial cells, in brain regions previously shown to undergo neurodegeneration, is consistent with a role for microglia in the phagocytosis of dead neurons and in actively contributing to the neurodegenerative process. The activation of astrocytes in regions that undergo neurodegeneration is also consistent with a role for these glial cells in the neurodegenerative process.

050100'03'05'07'09'11'13'15'17
Citations per Year

515 Citations

Semantic Scholar estimates that this publication has 515 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{German2002NeurodegenerationIT, title={Neurodegeneration in the Niemann-Pick C mouse: glial involvement.}, author={Dwight C. German and C L Liang and Tao Song and Umar Yazdani and Cindy Fang Xie and John M . Dietschy}, journal={Neuroscience}, year={2002}, volume={109 3}, pages={437-50} }