Specific induction of macrophage inflammatory protein 1‐α in glial cells of Sandhoff disease model mice associated with accumulation of N‐acetylhexosaminyl glycoconjugates

Abstract

Sandhoff disease is a lysosomal storage disease caused by simultaneous deficiencies of beta-hexosaminidase A (HexA; alphabeta) and B (HexB; betabeta), due to a primary defect of the beta-subunit gene (HEXB) associated with excessive accumulation of GM2 ganglioside (GM2) and oligosaccharides with N-acetylhexosamine residues at their non-reducing termini, and with neurosomatic manifestations. To elucidate the neuroinflammatory mechanisms involved in its pathogenesis, we analyzed the expression of chemokines in Sandhoff disease model mice (SD mice) produced by disruption of the murine Hex beta-subunit gene allele (Hexb-/-). We demonstrated that chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha) was induced in brain regions, including the cerebral cortex, brain stem and cerebellum, of SD mice from an early stage of the pathogenesis but not in other systemic organs. On the other hand, little changes in other chemokine mRNAs, including those of RANTES (regulated upon activation, normal T expressed and secreted), MCP-1 (monocyte chemotactic protein-1), SLC (secondary lymphoid-tissue chemokine), fractalkine and SDF-1 (stromal derived factor-1), were detected. Significant up-regulation of MIP-1alpha mRNA and protein in the above-mentioned brain regions was observed in parallel with the accumulation of natural substrates of HexA and HexB. Immunohistochemical analysis revealed that MIP-1alpha-immunoreactivity (IR) in the above-mentioned brain regions of SD mice was co-localized in Iba1-IR-positive microglial cells and partly in glial fibrillary acidic protein (GFAP)-IR-positive astrocytes, in which marked accumulation of N-acetylglucosaminyl (GlcNAc)-oligosaccharides was observed from the presymptomatic stage of the disease. In contrast, little MIP-1alpha-IR was observed in neurons in which GM2 accumulated predominantly. These results suggest that specific induction of MIP-1alpha might coincide with the accumulation of GlcNAc-oligosaccharides due to a HexB deficiency in resident microglia and astrocytes in the brains of SD mice causing their activation and acceleration of the progressive neurodegeneration in SD mice.

Extracellular uridine diphosphate-mediated microglial inflammation in a mouse model of Sandhoff disease

“…We demonstrated that MIP-1α is prominently upregulated in the brain of SD mice 22 , and that the basal production of MIP-1α is higher in microglia derived from SD mice (SD-Mg) than in that from wild-type mice (WTMg) 23 , suggesting that the higher MIP-1α production is due to the abnormal signal transduction caused by the deficiencies of HexA and HexB in SD-Mg as well as the effects of other neuronal cells, including neurons and astrocytes. We furthermore investigated whether or not extracellular nucleotides enhance the production of MIP-1α by SD-Mg. We found that UDP induces the production of MIP-1α in SD-Mg but not WT-Mg, while ATP has no effect on the production of MIP-1α by WT-or SD-Mg…”

“…We demonstrated that macrophage inflammatory protein-1α (MIP-1α) is upregulated in the brains of SD mice from the age of 1 week, and in microglial cells derived from neonatal SD mice 22,23 . Wu and Proia also demonstrated that the deletion of MIP-1α expression results in not only a substantial decrease in macrophage/microglial-associated pathology together with neuronal apoptosis in SD mice, but also an increase in the life span of SD mice 24 .…”

“…MIP-1α is a crucial factor for microglia-mediated neuroinflammation in the brain of SD mice, and the downregulation of the abnormal production of MIP-1α by microglia may delay the onset or progression of SD [22][23][24] . The activation of EP2 and 4/cAMP/PKA signaling has been shown as a potential target to control the abnormal production of MIP-1α in SD-Mg…”

Biomarkers of central nervous system inflammation in infantile and juvenile gangliosidoses

“…TNFR2 has been found to act as a neuroprotective agent in neurodegenerative disorders and is important for remyelination [10,11], and may be a response to neuroinflammation in these patients. MCP-1 and MIP-1α have been shown to be elevated in the CNS of murine Sandhoff disease in association with microglial activation; MIP-1α levels correlated with substrate accumulation, especially N-acetylglucosaminyl (GlcNAc)-oligosaccharide [12,13]. In sum, these elevated analytes are all cytokines associated with glial cell activation, and point to a mechanism of neuroinflammation [7][8][9][10][11][12][13].…”

“…MCP-1 and MIP-1α have been shown to be elevated in the CNS of murine Sandhoff disease in association with microglial activation; MIP-1α levels correlated with substrate accumulation, especially N-acetylglucosaminyl (GlcNAc)-oligosaccharide [12,13]. In sum, these elevated analytes are all cytokines associated with glial cell activation, and point to a mechanism of neuroinflammation [7][8][9][10][11][12][13]. We presume that these cytokines are derived from microglial cells in the central nervous system, and reflect primary pathology in nervous system tissues.…”