Multivariate neurocognitive and emotional profile of a mannosidosis murine model for therapy assessment.

alpha-Mannosidosis is a lysosomal storage disorder caused by lysosomal alpha-mannosidase (LAMAN) deficiency that leads to neurocognitive dysfunctions, psychotic symptoms and emotional changes in human patients. A murine mannosidosis model, LAMAN-deficient mice, was examined on a behavioral task battery that included test for neuromotor, exploratory and neurocognitive (spatial learning and memory) abilities, and multivariate statistical analyses were used to identify behavioral and neurocognitive domains that are most heavily affected by LAMAN deficiency. In addition, we further investigated synaptic plasticity recordings on hippocampal slices that may relate to these behavioral alterations. Correlation analysis revealed significant intra- and intertask correlations and factor analysis that included all 21 behavioral variables identified three main factors (exploration/emotionality, locomotion and learning/memory abilities). Significant correlations were observed between genotype, and factor 1 (exploration/emotionality) and factor 3 (learning/memory abilities). Discriminant function analysis showed that "path length in the open field test" and "time spent in the target quadrant during the water maze probe trial" were the most decisive variables to distinguish between the genotypes. We therefore suggest that these variables would be especially important in forthcoming therapy assessment experiments using this murine mannosidosis model. LAMAN-deficient mice displayed severe changes in synaptic plasticity, which may have contributed to the neurocognitive impairments observed. The present report further shows that targeted deletion of the LAMAN gene in mice mimics many aspects of human alpha-mannosidosis, and these data provide a basis for future therapeutic experiments.

Efficacy of enzyme replacement therapy in alpha-mannosidosis mice: a preclinical animal study.

Alpha-mannosidosis is a lysosomal storage disorder which manifests itself in the excessive storage of mannose-containing oligosaccharides in the lysosomes of multiple peripheral tissues and in the brain. Here we report on the correction of storage in a mouse model of alpha-mannosidosis after intravenous administration of lysosomal acid alpha-mannosidase (LAMAN) from bovine kidney, and human and mouse recombinant LAMAN. The bovine and the human enzyme were barely phosphorylated, whereas the bulk of the mouse LAMAN contained mannose 6-phosphate recognition markers. The clearance decreased from bovine to human to mouse LAMAN with plasma half-times of 4, 8 and 12 min, respectively. The apparent half-life of the internalized enzyme was dependent on the enzyme source as well as tissue type and varied between 3 and 16 h. The corrective effect on the storage of neutral oligosaccharides was time-, tissue- and dose-dependent, and the effects were observed to be transient. After a single dose of LAMAN the maximum corrective effect was observed between 2 and 6 days after injection. In general the corrective effect of the human LAMAN was higher than that of the mouse LAMAN and lowest for the bovine LAMAN. Injection of 250 mU human LAMAN/g body weight followed by a subsequent injection 3.5 days later was sufficient to clear liver, kidney and heart from neutral oligosaccharides. Surprisingly a decrease in mannose containing oligosaccharides was also observed in the brain, with storage levels reported at <30% than that found in controls. These data clearly underline the efficacy of enzyme replacement therapy for the correction of storage in alpha-mannosidosis and suggest that this treatment can substantially decrease storage in the brain.