Mouse Genome Informatics
cx
    Npc1m1N/Npc1m1N
Tg(PRNP-APPSweInd)8Dwst/0

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 have a maximum lifespan of 77 days, with mortality rate increasing drastically from 55 days onward
• 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 103 days versus 69 days

growth/size/body
• mutants reach a maximum body weight of approximately 12 grams by 6 weeks of age which is about 30% less compared to controls
• weight declines progressively after 6 weeks of age until death

behavior/neurological
• mutants exhibit deficits in object memory index at 7 and 10 weeks of age; object recognition memory deficits are accelerated compared to single Npc1 homozygotes
• 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 7 weeks of age which is further exacerbated by 10 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 both 7 and 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 at a higher level than in single Npc1 homozygotes
• 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
• mutants exhibit a profound increase in the number and activation of glial fibrillary acidic protein (GFAP)-labeled astrocytes in the hippocampus and cerebellum compared with wild-type, single Tg(PRNP-APPSweInd)8Dwst mutants, and single Npc1 homozygotes
• mutants treated with 2-HPC at P7 to lower cholesterol accumulation show decreased astrocyte activation compared to saline-injected mutants
• neurodgeneration in the cerebellum is accelerated compared to single Npc1 homozygotes
• decrease in the number of cerebellar Purkinje cells that is more pronounced than in single Npc1 homozygotes
• however neuronal loss in the hippocampus is not seen
• mutants exhibit a loss of myelin fibre tracts in the hippocampus/cortex and cerebellum, indicating significant demyelination; demyelination is more severe than in single Npc1 homozygotes

hematopoietic system
• mutants exhibit microglial activation in the hippocampus and cerebellum at a higher level than in single Npc1 homozygotes
• 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 are higher in the hippocampus and the cerebellum than in controls, including single Npc1 homozygotes
• cytosolic cathepsin D, cytochrome c and Bcl-2-associated X protein levels are increased in the cerebellum to a higher level than in single Npc1 homozygotes
• 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
• cathepsin D activity is higher in the hippocampus and the cerebellum than in controls, including single Npc1 homozygotes

immune system
• mutants exhibit microglial activation in the hippocampus and cerebellum at a higher level than in single Npc1 homozygotes
• 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)
Alzheimer Disease; AD 104300 J:188345
Niemann-Pick Disease, Type C1; NPC1 257220 J:188345