Developmentally regulated mannose 6-phosphate receptor-mediated transport of a lysosomal enzyme across the blood-brain barrier

Mucopolysaccharidosis type VII is a lysosomal storage disorder resulting from inherited deficiency of beta-glucuronidase (GUS). Mucopolysacchariclosis type VII is characterized by glycosaminoglycan storage in most tissues, including brain. In these disorders, enzyme delivery across the blood-brain barrier (BBB) is the main obstacle to correction of lysosomal storage in the CNS. Prior studies suggested mouse brain is accessible to GUS in the first 2 weeks of life but not later. To explore a possible role for the mannose 6-phosphate/insulin-like growth factor II receptor in GUS transport across the BBB in neonatal mice, we compared brain uptake of phosphorylated GUS (P-GUS) and nonphosphorylated GUS (NP-GUS) in newborn and adult mice. I-131-P-GUS was transported across the BBB after i.v. injection in 2-day-old mice. The brain influx rate (K-in) of I-131-P-GUS in 2-day-old mice was 0.21 mul/g(.)min and decreased with age. By 7 weeks of age, transport of I-131-P-GUS was not significant. Capillary depletion revealed that 62% of the I-113-P-GUS in brain was in brain parenchyma in 2-day-old mice. In addition, uptake of I-131-P-GUS into brain was significantly reduced by coinjection of unlabeled P-GUS or M6P in a dose-dependent manner. In contrast, the Kin of I-131-NP-GUS (0.04 mul/g(.)min) was significantly lower than I-131-P-GUS in 2-day-old mice. Transcardiac brain perfusion confirmed that neither I-131-P-GUS nor I-131-NP-GUS crossed the BBB in adult mice. These results indicate that I-131-p-GUS transport into brain parenchyma in early postnatal life is mediated by the mannose 6-phosphate/insulin-like growth factor 11 receptor. This receptor-mediated transport is not observed in adult mice.