title: 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.
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA. dwight.german@utsouthwestern.edu
authors.forename: D C
authors.initials: DC
authors.lastname: German
authors.forename: C-L
authors.initials: CL
authors.lastname: Liang
authors.forename: T
authors.initials: T
authors.lastname: Song
authors.forename: U
authors.initials: U
authors.lastname: Yazdani
authors.forename: C
authors.initials: C
authors.lastname: Xie
authors.forename: J M
authors.initials: JM
authors.lastname: Dietschy
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D002402:Cathepsin D / Q000378:metabolism*; D002452:Cell Count; D048429:Cell Size / Q000502:physiology; D003337:Corpus Callosum / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D017628:Microglia / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008854:Microscopy, Electron; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D014855:Wallerian Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D002402:Cathepsin D