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 disease, is a severe disorder of the central and peripheral nervous system caused by the absence galactocerebrosidase (GALC) activity. This autosomal recessive disease affects humans and has been described in a number of mammalian species including the rhesus monkey. In this report, the clinical pathological, immunohistochemical and immunohistological features observed in Krabbe-affected rhesus macaques are described. Upon microscopic examination, the cerebral and cerebellar white matter was infiltrated by mononuclear and multinucleated globoid cells associated with lack of myelin. Using immunohistochemistry and multilabel confocal microscopy with multiple cell-type specific markers, it was determined that both the small and large-size globoid cells were CD68+, HAM56+, LN5+, CD163, IBA-1 and Glut-5 suggesting a microglial origin. Increased expression of inducible nitric oxide synthase (iNOS) was expressed in affected white matter and localized within activated microglia and globoid cells. Increased frequency of activation of microglia in affected areas may play an important role in the pathogenesis of globoid cell leukodystrophy. The presence and increased expression of iNOS seems to be preferentially toxic to oligodendrocytes or myelin.