Sites and temporal changes of gangliosides GM1/GM2 storage in the Niemann-Pick disease type C mouse brain

Niemann-Pick disease type C (NPC) is a progressive neurodegenerative disorder with characteristic storage of glycolipids in the brain. This study investigated cellular origin and temporal changes of monosialoganglioside storage in the Balb/c npc(nih) mouse brain by immunohistochemistry. Anti-GM1 gave positive staining of the hippocampus, thalamus, cerebellar molecular and Purkinje cell layers in the 3-week old NPC mouse brain and in general, the staining progressively diminished in an age-dependent manner. Anti-GM2 gave positive staining of the hippocampus, thalamus, cerebellar granule cell layer and brainstem nuclei in the 3-week old NPC mouse brain. In contrast to GM1, GM2 staining in these regions, except for the hippocampus, progressively augmented in an age-dependent manner. Double labeling experiments with antibodies against glial fibrillary acidic protein and lysozyme showed localization of GM1 and GM2 in reactive astrocytes and macrophages, respectively. Thus in the NPC mouse brain, GM1 accumulated primarily in neurons and astrocytes whereas GM2 accumulated primarily in neurons and macrophages. Temporal profiles of storage were different from each other and depended on the cell type, presumably reflecting both developmental changes and progression of the disease process. We also investigated subcellular sites of storage in primary-cultured Purkinje cells from the neonatal NPC mouse by immunocytochemistry. In NPC Purkinje cells, GM1 accumulated both in the cytoplasm and dendrites whereas GM2 showed punctuate accumulation in perinuclear vesicles. Thus, subcellular sites of storage were also different between GM1 and GM2 in NPC neurons.