Mouse Genome Informatics
hm
    Npc1m1N/Npc1m1N
involves: BALB/c * C3H/HeJ * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
• mutants exhibit a reduced lifespan with only 30% of mice living past 90 days
• mutants treated with 2-hydroxypropyl-beta-cyclodextrin (2-HPC) at P7 to lower cholesterol accumulation live significantly longer than saline-injected mutants, with a median survival of 107 days versus 85 days

behavior/neurological
• mutants exhibit deficits in object memory index at 10 weeks of age, but not at 7 weeks of age, on the object recognition memory test
• mutants treated with 2-HPC at P7 to lower cholesterol accumulation show significant improvement in cognitive performance
• mutants exhibit impaired rotarod performance and gait coordination at 10 weeks of age but not at 4 or 7 weeks of age
• mutants treated with 2-HPC at P7 to lower cholesterol accumulation show significant improvement in motor performance
• mutants exhibit reduced locomotor activity and increased periods of inactivity in open-field tests at 10 weeks of age
• mutants treated with 2-HPC at P7 to lower cholesterol accumulation show significant improvement in motor performance

nervous system
• mutants exhibit microglial activation in the hippocampus and cerebellum, however at a lower level than in double Npc1 and Tg(PRNP-APPSweInd)8Dwst mutants
• mutants treated with 2-HPC at P7 to lower cholesterol accumulation show lower microglia activation compared to saline-injected mutants
• mutants exhibit intracellular accumulation of unesterified cholesterol in the hippocampus and cerebellum at 4, 7, and 10 weeks of age
• however total cholesterol content in the hippocampus and cerebellum is not altered compared with controls
• neurodgeneration in the cerebellum
• mutants treated with 2-HPC at P7 to lower cholesterol accumulation show decreased Purkinje cell loss compared to saline-injected mutants
• decrease in the number of cerebellar Purkinje cells; cell loss is less pronounced than in double Npc1 and Tg(PRNP-APPSweInd)8Dwst mutants
• however neuronal loss in the hippocampus is not seen
• mutants exhibit demyelination in the hippocampus/cortex and cerebellum, however demyelination is less severe than in double Npc1 and Tg(PRNP-APPSweInd)8Dwst mutants at earlier stages

hematopoietic system
• mutants exhibit microglial activation in the hippocampus and cerebellum, however at a lower level than in double Npc1 and Tg(PRNP-APPSweInd)8Dwst mutants
• mutants treated with 2-HPC at P7 to lower cholesterol accumulation show lower microglia activation compared to saline-injected mutants

homeostasis/metabolism
• cathepsin D levels and activity are higher in the hippocampus and the cerebellum than in controls, although this is lower than in double Npc1 and Tg(PRNP-APPSweInd)8Dwst mutants
• cytosolic cathepsin D, cytochrome c and Bcl-2-associated X protein levels are increased in the cerebellum although to a lower level than in double Npc1 and Tg(PRNP-APPSweInd)8Dwst mutants
• mutants exhibit intracellular accumulation of unesterified cholesterol in the hippocampus and cerebellum at 4, 7, and 10 weeks of age
• however total cholesterol content in the hippocampus and cerebellum is not altered compared with controls

immune system
• mutants exhibit microglial activation in the hippocampus and cerebellum, however at a lower level than in double Npc1 and Tg(PRNP-APPSweInd)8Dwst mutants
• mutants treated with 2-HPC at P7 to lower cholesterol accumulation show lower microglia activation compared to saline-injected mutants

Mouse Models of Human Disease
OMIM IDRef(s)
Niemann-Pick Disease, Type C1; NPC1 257220 J:188345