Mouse Genome Informatics
cx1
    Azdm1A/J/Azdm1A/J
Tg(PRNP-APPSweInd)8Dwst/0

involves: A/J * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• decreased brain amyloid-beta 40 and 42

other phenotype
• decreased brain amyloid burden
• decreased brain amyloid plaque number
• decreased brain amyloid-beta 40 and 42


Mouse Genome Informatics
cx2
    Azdm1A/J/Azdm1C57BL/6J
Tg(PRNP-APPSweInd)8Dwst/0

involves: A/J * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• decreased brain amyloid-beta 40 and 42

other phenotype
• decreased brain amyloid burden
• decreased brain amyloid plaque number
• decreased brain amyloid-beta 40 and 42


Mouse Genome Informatics
cx3
    Azdm2A/J/Azdm2C57BL/6J
Tg(PRNP-APPSweInd)8Dwst/0

involves: A/J * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
other phenotype
• decreased brain amyloid burden
• decreased brain amyloid plaque number


Mouse Genome Informatics
cx4
    Azdm2A/J/Azdm2A/J
Tg(PRNP-APPSweInd)8Dwst/0

involves: A/J * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
other phenotype
• decreased brain amyloid burden
• decreased brain amyloid plaque number


Mouse Genome Informatics
cx5
    Azdm3A/J/Azdm3C57BL/6J
Tg(PRNP-APPSweInd)8Dwst/0

involves: A/J * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
other phenotype
• decreased brain amyloid burden
• decreased brain amyloid plaque number


Mouse Genome Informatics
cx6
    Azdm3A/J/Azdm3A/J
Tg(PRNP-APPSweInd)8Dwst/0

involves: A/J * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
other phenotype
• decreased brain amyloid burden
• decreased brain amyloid plaque number


Mouse Genome Informatics
cx7
    Azdm4A/J/Azdm4C57BL/6J
Tg(PRNP-APPSweInd)8Dwst/0

involves: A/J * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
other phenotype
• decreased brain amyloid plaque number


Mouse Genome Informatics
cx8
    Azdm4A/J/Azdm4A/J
Tg(PRNP-APPSweInd)8Dwst/0

involves: A/J * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
other phenotype
• decreased brain amyloid plaque number


Mouse Genome Informatics
cx9
    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
• 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 Genome Informatics
cx10
    Atp7btx-J/Atp7btx-J
Tg(PRNP-APPSweInd)8Dwst/0

involves: C3H/HeJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• survival is increased compared to in Tg(PRNP-APPSweInd)8Dwst mice (J:86701)

homeostasis/metabolism
• copper levels are increased compared to in heterozygous Atp7btx-J mice

nervous system
• mice exhibit a 45% reduction in plaque area compared to in Tg(PRNP-APPSweInd)8Dwst mice due to a reduction in the number of plaques

other phenotype
• mice exhibit a 45% reduction in plaque area compared to in Tg(PRNP-APPSweInd)8Dwst mice due to a reduction in the number of plaques


Mouse Genome Informatics
cx11
    Tg(Camk2a-ITM2B)8.4Ldad/0
Tg(PRNP-APPSweInd)8Dwst/0

involves: C3H/HeJ * C57BL/6J * FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• reduction in plaque formation compared to mice carrying just Tg(PRNP-APPSweInd)8Dwst

other phenotype
• reduction in plaque formation compared to mice carrying just Tg(PRNP-APPSweInd)8Dwst


Mouse Genome Informatics
cx12
    Tg(PRNP-APPSweInd)8Dwst/0
Tg(PSEN1*L286V)1274Citr/0

involves: C3H/HeJ * C57BL/6J * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
other phenotype
• amyloid deposition is enhanced when the PSEN1 transgene is also expressed by mutants; deposition is noted by 30-45 days of age


Mouse Genome Informatics
cx13
    Tg(PRNP-APPSweInd)8Dwst/0
Tg(PSEN1)1098Citr/0

involves: C3H/HeJ * C57BL/6J * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
other phenotype
• amyloid deposition is enhanced when the PSEN1 transgene is also expressed by mutants; deposition is noted by 30-45 days of age


Mouse Genome Informatics
tg14
    Tg(PRNP-APPSweInd)8Dwst/0
involves: 129S6/SvEvTac * 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
• Background Sensitivity: survival decreases to 25-40% within 120 days of life; only 17% (7/41) survive to 365 days


Mouse Genome Informatics
tg15
    Tg(PRNP-APPSweInd)8Dwst/0
involves: C3H/HeJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• copper levels are decreased compared to in non-transgenic mice


Mouse Genome Informatics
tg16
    Tg(PRNP-APPSweInd)8Dwst/0
involves: C3H/HeJ * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Increase in creatine deposits in hippocampus of Tg(PRNP-APPSweInd)8Dwst/0 mice with age

mortality/aging
• Background Sensitivity: 20/52 mice die before 120 days, 3/52 by 130 days and 3/52 die after 250 days; 50% survive for at least a year

behavior/neurological
• mice show impairment in acquisition of spatial information during place discrimination training at 11 weeks of age; mice show longer latencies to reach escape platform and longer search paths to reach platform
• during probe trial after completion of training, mice display lower annulus crossing index, searching for platform in a circular fashion and often crossing the centers of alternative quadrants, relative to non-transgenic controls

nervous system
N
• no differences are seen in volume of dorsal hippocampus or in neuronal cytoarchitecture between transgenic and control mice (J:69967)
• by 101 days, plaques are detected within the pial vessels, and in the cerebral vasculature by 196 days
• amyloid plaques are associated with dystrophic neurites; dystrophic neuron pathology increases with age and frequency of large cored plaques
• dense-cored amyloid deposits contain amyloid beta-42 peptide (J:69967)
• 14-month old mutants show dense amyloid beta core plaques in the hippocampus (J:166801)

other phenotype
• potent deposition of cerebral amyloid is observed in all mice 90 days of age
• by 101 days, plaques are detected within the pial vessels, and in the cerebral vasculature by 196 days
• dense-cored amyloid deposits contain amyloid beta-42 peptide (J:69967)
• 14-month old mutants show dense amyloid beta core plaques in the hippocampus (J:166801)

homeostasis/metabolism
• increase in creatine deposits in the hippocampal gray matter as mutants age

Mouse Models of Human Disease
OMIM IDRef(s)
Alzheimer Disease; AD 104300 J:166801


Mouse Genome Informatics
tg17
    Tg(PRNP-APPSweInd)8Dwst/0
involves: C3H/HeJ * C57BL/6J * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• Background Sensitivity: survival decreases to 25-40% within 120 days of life; only 3/12 mice survive to 365 days
• survival is less than on other genetic backgrounds examined


Mouse Genome Informatics
tg18
    Tg(PRNP-APPSweInd)8Dwst/?
involves: 129S6/SvEvTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• observed at 16 and 20 weeks of age in hippocampus and cortex
• level of brain amyloid beta peptide 42 is predominant over 40; levels increase dramatically after 16 weeks of age

homeostasis/metabolism
• elevated plasma triglyceride levels observed between 9 and 15 weeks of age
• VLDL production rates are increased as early as 9 weeks of age and remain elevated up to 22 weeks of age
• plasma free fatty acid levels were unchanged

other phenotype
• observed at 16 and 20 weeks of age in hippocampus and cortex
• level of brain amyloid beta peptide 42 is predominant over 40; levels increase dramatically after 16 weeks of age

Mouse Models of Human Disease
OMIM IDRef(s)
Alzheimer Disease; AD 104300 J:113199