IMMUNOPATHOLOGIC ALTERATIONS IN RHESUS MACAQUES WITH GLOBOID CELL LEUKODYSTROPHY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Globoid cell leukodystrophy or Krabbe's disease, is a severe disorder of the central and peripheral nervous system caused by the absence galactocerebrosidase (GALC) activity. In this report, the clinical neuropathological, histochemical and immunohistological features observed in Krabbe-affected rhesus macaques are described. Clinical signs in affected animals include pronounced muscle tremors of head and limbs, difficulty ambulating, ataxia, hypermetria and respiratory difficulties. Histopathologically, all animals presented with evidence of demyelination in the peripheral and central nervous system and accumulation of mononuclear and multinuclear globoid cells in the cerebral and cerebellar white matter associated with severe gliosis. Using immunohistochemistry and multilabel confocal microscopy with multiple cell-type specific markers, it was determined that globoid cells were CD68+, HAM56+, LN5+, CD163+, IBA-1+ and Glut-5+ suggesting that both peripheral blood derived monocyte/macrophages and resident parenchymal microglia give rise to globoid cells. Interestingly, many of the globoid cells as well as parenchymal microglia with a more ameboid morphology expressed HLA-DR indicating immune activation. Furthermore, a marked increase in expression of iNOS was observed in the affected white matter and colocalized with globoid cells and activated microglia. This raises the possibility that dysregulation of monocyte/macrophage/microglia may contribute to the pathogenesis of Krabbe's disease.