Overview

Mice homozygous for the Apoe^tm1Unc mutation on the DBA/2J background may be useful in studies of diet-induced obesity without diabetes, Alzheimer's Disease, neurodegeneration, atherosclerosis and hypercholesterolemia.

Donating Investigator

IMR Colony, The Jackson Laboratory

Genetic overview

Genetic Background	Generation

Apoe^tm1Unc

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Apoe	apolipoprotein E

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Research Applications

Cardiovascular Research
Mouse/Human Gene Homologs
Neurobiology Research
Diabetes and Obesity Research

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Details

Detailed Description

Mice homozygous for the Apoe^tm1Unc mutation show a marked increase in total plasma cholesterol levels that are unaffected by age or sex. Fatty streaks in the proximal aorta are found at 3 months of age. The lesions increase with age and progress to lesions with less lipid but more elongated cells, typical of a more advanced stage of pre-atherosclerotic lesion. Moderately increased triglyceride levels have been reported in mice with this mutation on a mixed C57BL/6 x 129 genetic background. Aged APOE deficient mice (>17 months) have been shown to develop xanthomatous lesions in the brain consisting mostly of crystalline cholesterol clefts, lipid globules, and foam cells. Smaller xanthomas were seen in the choroid plexus and ventral fornix. Recent studies indicate that APOE deficient mice have altered responses to stress, impaired spatial learning and memory, altered long term potentiation, and synaptic damage.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for the strain above. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Development

The Apoe^tm1Unc mutant strain was developed in the laboratory of Dr. Nobuyo Maeda at The University of North Carolina at Chapel Hill. The 129-derived E14Tg2a ES cell line was used. The plasmid used is designated as pNMC109 and the founder line is T-89 in the primary reference. The mice were backcrossed to C57BL/6J for 10 generation and then backcrossed to DBA/2J for 5 generations (using a speed congenic protocol) before being made homozygous.

Control Suggestions

Wild-type from the colony
000671 DBA/2J

Additional Information

Considerations for Choosing Controls

Selected References

Piedrahita JA; Zhang SH; Hagaman JR; Oliver PM; Maeda N. 1992. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc Natl Acad Sci U S A 89(10):4471-5PubMed: 1584779 MGI: J:1050

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Genetics

Apoe^tm1Unc

Allele Symbol: Apoe^tm1Unc

Allele Name	targeted mutation 1, University of North Carolina
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	AopE(-); apoE-; APOE KO; Apoe^tm1Un; apoE0; ApoE-KO; EKO; epsilon-; mE^-; mEKO
Gene Symbol and Name	Apoe, apolipoprotein E
Gene Synonym(s)
Strain of Origin	129P2/OlaHsd
Chromosome	7
Molecular Note	Insertion of a neomycin resistance cassette deleted part of exon 3 and part of intron 3 of the Apoe gene. Plasma from homozygous mutant mice gave no detectable immunoprecipitate by the Ouchterlony double immunodiffusion test using a rabbit antibody to rat APOE.
Mutations Made By	Dr. Nobuyo Maeda, University of North Carolina at Chapel Hill

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Apoe^tm1Unc related

Cardiovascular Research
- Hypercholesterolemia
- Atherosclerosis
Mouse/Human Gene Homologs
- hyperlipoproteinemia, type III
- Alzheimer's

Neurobiology Research
- Behavioral and Learning Defects
- Neurodegeneration
- Alzheimer's Disease
  - APOE mutants
Diabetes and Obesity Research
- Obesity Without Diabetes
  - diet-induced

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
B6.129P2-Apoe/J

behavior/neurological phenotype

abnormal spatial learning
- longer latency to find the platform in Morris maze tests
- slow to acquire a preference for the target quadrant and the magnitude of the preference is always less than controls

increased thigmotaxis
- elevated thigmotaxis in Morris maze tests

immune system phenotype

abnormal B cell activation
- spleen cells display polyclonal B cell activation, with increased expression of MHC II, Fas, and CD86 and lower expression of CD21, CD22, and CD23

abnormal CD4-positive, alpha beta T cell number
- clusters of CD4+ cells found in fatty streak lesions
- ratio of Th2 to Th1 cells is increased from 4.4 to 11.4 on a normal diet and up to 20.9 on a high cholesterol diet

abnormal immune serum protein physiology

abnormal immune system morphology

abnormal immune system physiology

abnormal T cell number
- increased numbers of cytokine producing T cells

decreased follicular B cell number
- decreased relative to controls

decreased interferon-gamma secretion
- production is reduced when fed a high cholesterol diet

decreased marginal zone B cell number
- with induction of SLE by cGVH, levels are slightly decreased compared to wild-type

decreased susceptibility to type IV hypersensitivity reaction
- decreased antigen specific delayed hypersensitivity response

increased anti-double stranded DNA antibody level
- after induction of cGVH-SLE, mice display greatly increased levels compared to wild-type controls or non-cGVH-SLE mutants

increased anti-nuclear antigen antibody level
- after induction of cGVH-SLE, mice display greatly increased levels of anti-chromatin antibodies compared to wild-type controls or non-cGVH mutants

increased autoantibody level
- after induction of cGVH-SLE, IgG and IgM anti-oxidized LDL and anti-cardiolipin antibodies are increased compared to wild-type or Apoe-null controls

increased B cell number
- newly formed B cells are significantly increased compared to wild-type

increased IgM level
- IgM response to tetanus toxoid is significantly increased as compared to controls

increased immunoglobulin level
- mutants with cGVH-induced SLE show greatly increased levels compared to wild-type controls or untreated mutants

increased marginal zone B cell number
- increased 2-fold compared to wild-type

increased spleen weight
- increased spleen weight while the thymus weight remains normal

increased susceptibility to systemic lupus erythematosus

increased T-helper 2 cell number

vascular inflammation
- aortae show macrophage and T cell extravasation within atherosclerotic lesions

integument phenotype

skin lesions
- progressive skin lesions, mainly seen as eruptive xanthomas on shoulder and back areas with lipids and extracellular matix as the predominant components

liver/biliary system phenotype

abnormal liver physiology
- hepatic uptake of LDL is increased two fold
- no significant change in serum alanine transaminase with high fat diet as is seen in controls (marker for liver damage)

mortality/aging

premature death
- 35% dead by 18 months

muscle phenotype

decreased vasodilation
- homozygotes fed a normal or atherosclerotic diet show severely impaired endothelium-dependent relaxation to acetylcholine in aortic rings relative to age-matched C57BL/6J control mice

impaired muscle relaxation
- maximal response to acetylcholine is considerably reduced
- relaxation response to acetylcholine in blood vessels is significantly attenuated at 13 months of age

nervous system phenotype

abnormal blood-brain barrier function
- impaired blood-brain barrier and blood-nerve barrier as indicated by extensive extravasation of serum proteins into sciatic nerve, spinal cord and cerebellum and occasional extravasation into cortex and subcortex

cochlear ganglion degeneration
- at 24 weeks, homozygotes fed a normal diet show a reduced number of spiral ganglion cells in the basal turn of the cochlea
- loss of ganglion cells is excerbated by an atherosclerotic diet

cochlear inner hair cell degeneration
- at 24 weeks, homozygotes fed a normal diet show almost complete loss of IHCs in the basal turn and some IHC loss in the middle turn
- IHC loss at the base turn is exacerbated by an atherosclerotic diet

cochlear outer hair cell degeneration
- at 24 weeks, homozygotes fed a normal diet show almost complete loss of OHCs in the basal turn and some OHC loss in the middle turn
- OHC loss at the base turn is exacerbated by an atherosclerotic diet

renal/urinary system phenotype

abnormal kidney arterial blood vessel morphology
- arterioles of the vascular pole show a "foamy" degeneration of smooth muscle cells

abnormal renal glomerulus morphology
- glomerular cell numbers are increased
- increased glomerular tuft area

dilated glomerular capillary
- at times mesangiolysis is associated with ballooning dilatation ("microaneurysm") of adjacent glomerular capillaries

expanded mesangial matrix
- progressive increase in glomerular matrix, already evident at 24 weeks, associated with accumulation of laminin and collagen IV

glomerular capillary thrombosis
- lipid droplets filling glomerular capillary lumina at 36 weeks in about 50% of mice
- such thrombus-like structures commonly dsiplay a laminated appearance with adjacent foam cells in the mesangium

kidney microaneurysm
- at times mesangiolysis is associated with ballooning dilatation ("microaneurysm") of adjacent glomerular capillaries

mesangiolysis
- loss of mesangial matrix sometimes at 36 weeks but never at 24 weeks or in controls

renal glomerulus lipidosis
- glomerular foam cells in the mesangium, capillary lumina and within the glomerular stalk close to the vascular pole
- lipid deposits in arteriolar walls in the vascular poles
- lipid droplets filling glomerular capillary lumina at 36 weeks in about 50% of mice

respiratory system phenotype

abnormal lung hysteresivity
- percent increase in hysteresivity with age greater than in controls

abnormal lung volume
- lung volume similar to controls at 3 months but 2.5 fold greater at 8 months of age

abnormal pulmonary alveolus morphology
- fewer but larger alveoli at 3 months of age
- less surface area to volume

increased airway resistance
- resistance to airflow greater than controls at 3 months but not at 8 months of age

increased lung compliance
- dynamic and static compliance greater than controls at 8 months of age

skeleton phenotype

abnormal bone structure

abnormal osteoblast physiology
- increased rate of bone formation

abnormal skeleton physiology

increased bone mineral density
- higher bone mineralization density in vertebral bodies
- increased bone volume to tissue volume ratio

increased bone trabecula number
- increased number of trabeculae

increased compact bone thickness
- in vertebral bodies and tibia

taste/olfaction phenotype

impaired olfaction
- latency to taste vanillin-cued quinine significantly increased only at day 5
- preference for plain water over 0.1% iso-amyl alcohol moderate compared to the strong preference shown by controls
- slower than control to find buried food pellet although found pellets visually more rapidly

vision/eye phenotype

abnormal eye electrophysiology
- implicit times increased for a and b waves of dark adapted electroretinogram
- wave amplitudes attenuated for a and b waves of dark adapted electroretinogram

abnormal retinal inner nuclear layer morphology
- perinuclear vacuolation on a high cholesterol diet

thin retinal inner nuclear layer
- cell numbers reduced

thin retinal outer nuclear layer
- cell numbers reduced

cardiovascular system phenotype

abnormal aorta wall morphology
- Cx43 distribution at cell-cell junction shows significant disruption
- endothelial nitric oxide synthase (eNOS) in mutant aortic wall is distinctly reduced

abnormal blood flow velocity
- anesthetized homozygotes show significantly increased transaortic blood velocities relative to wild-type mice with peak aortic velocity at 133.4 ¿ 7.8 cm/s vs 89.2 ¿ 5.8 cm/s, and mean aortic velocity at 35.9 ¿ 2.7 vs 22.0 ¿ 1.6 cm/s, respectively
- however, homozygotes show alterations in aortic arch acceleration suggestive of increased peripheral wave reflections
- in addition, anesthetized homozygotes show significantly increased transmitral blood velocities relative to wild-type mice with peak mitral velocities at 92 ¿ 7.2 cm/s vs 47.2 ¿ 5.3 cm/s, and mean mitral velocities at 20.6 ¿ 1.7 vs 11.4 ¿ 1.3 cm/s, respectively
- no significant differences in heart rate, peak aortic acceleration or ejection time are observed in the conscious or anesthetized state, when normalized to body weight
- tively

abnormal blood vessel physiology
- pulse wave velocity is insignificantly elevated at 4 months
- pulse wave velocity significantly elevated at 13 months

abnormal blood-brain barrier function
- impaired blood-brain barrier and blood-nerve barrier as indicated by extensive extravasation of serum proteins into sciatic nerve, spinal cord and cerebellum and occasional extravasation into cortex and subcortex

abnormal kidney arterial blood vessel morphology
- arterioles of the vascular pole show a "foamy" degeneration of smooth muscle cells

abnormal spiral modiolar artery morphology
- homozygotes fed an atherosclerotic diet develop atherosclerotic alterations in the spiral modiolar artery (SMA)
- in contrast, no such changes are detected in the SMA of homozygotes fed a normal diet

arteriosclerosis
- homozygotes exhibit a 13% increase in aortic pulse-wave velocity (PWV) relative to wild-type mice (428 ¿ 14.5 cm/s vs 379 ¿ 10.1 cm/s), indicating increased arterial stiffness and reduced vascular elasticity

atherosclerotic lesions
- 23% of luminal surface in the aortic arch and thoracic aorta is covered by plaques at 4 months of age
- 61% covered by plaques at 13 months of age
- advanced atherosclerotic lesions; massive atheromas with abundant cholesterol crystals, neutral lipids, and diminished extracellular matrix in arotic roots and coronary arteries
- aortic lesions are observed in aortic sinus at level of aortic valve leaflets; lesions are about 27% of total aortal area
- at 13 months, homozygotes display atherosclerotic lesions extending from the carotid arteries, heart, and aorta down to the renal arteries and the iliac bifurcation
- at 24 weeks of age, homozygotes fed a normal diet (but not similarly-fed C57BL/6J control mice) show obvious atherosclerotic lesions in the aortic sinus and ascending aorta
- focal fragmentation of elastic laminae
- intimal lesions are observed in atherosclerotic aortas in mutants
- lesions are most severe in the proximal aorta and at the bifurcation of carotid arteries; the proximal carotid arteries are relatively free of lesions
- lesions comprise around 14-16% of total aortic arch area in male and female mutants
- major lesions are observed on lesser curvature of aortic arch in males and females with minor lesions found at branches of aortic arch
- plaques in the luminal surface of the aorta are significantly larger in atherosclerotic diet homozygotes than in normal diet homozygotes
- regular exercise does not reduce atherosclerotic lesion formation in homozygotes, as shown by a comparable % oil red-O staining of whole aortas from sedentary and exercised mutant mice
- the number of atherosclerotic lesions in aortic sinus and ascending aorta is significantly increased in homozygotes fed an atherosclerotic diet vs a normal diet
- thickened intima, foam cell accumulation and thin collagen cap

cardiac hypertrophy
- at 13 months, homozygotes show a 59% increase in heart weight-to-body weight ratio relative to wild-type mice

decreased susceptibility to atherosclerosis
- in perhexiline-treated mice fed a high-fat diet

decreased systemic vascular resistance
- under anesthesia, homozygotes appear to exhibit significantly reduced peripheral vascular resistance and compliance in the presence of normal blood pressures

decreased vasodilation
- homozygotes fed a normal or atherosclerotic diet show severely impaired endothelium-dependent relaxation to acetylcholine in aortic rings relative to age-matched C57BL/6J control mice

dilated glomerular capillary
- at times mesangiolysis is associated with ballooning dilatation ("microaneurysm") of adjacent glomerular capillaries

glomerular capillary thrombosis
- lipid droplets filling glomerular capillary lumina at 36 weeks in about 50% of mice
- such thrombus-like structures commonly dsiplay a laminated appearance with adjacent foam cells in the mesangium

increased cardiac output
- under anesthesia, homozygotes exhibit elevated flow velocities suggesting elevated cardiac output

increased cardiac stroke volume
- under anesthesia, homozygotes appear to exhibit significantly increased stroke volume

increased heart weight
- at 13 months, homozygotes show a 23% increase in heart weight relative to wild-type mice (186 ¿ 7.1 vs. 151 ¿ 2.5 mg)

increased susceptibility to atherosclerosis
- on a high fat, high cholesterol diet, mutants exhibit moderate to severe aortic and carotid atherosclerosis
- severity of atherosclerosis is 2-fold and 99-fold higher in atherosclerotic diet homozygotes than in normal diet homozygotes and C57BL/6J control mice, respectively

kidney microaneurysm
- at times mesangiolysis is associated with ballooning dilatation ("microaneurysm") of adjacent glomerular capillaries

spiral modiolar artery stenosis
- lumen stenosis of the spiral modiolar artery in the cochlea is exacerbated by an atherosclerotic diet relative to a normal diet

vascular inflammation
- aortae show macrophage and T cell extravasation within atherosclerotic lesions

vascular stenosis
- vascular stenosis is significantly increased in homozygotes fed an atherosclerotic diet vs a normal diet

cellular phenotype

abnormal osteoblast physiology
- increased rate of bone formation

increased cholesterol efflux
- in perhexiline-treated mice fed a high-fat diet

oxidative stress
- in contrast, regular exercise results in reduced mitochondrial damage and oxidant load and increased SOD2 and adenine nucleotide translocator activities in normocholesterolemic control mice
- regular exercise fails to reduce endogenous oxidant load and mitochondrial damage in hypercholesterolemic mutant mice

growth/size/body region phenotype

cardiac hypertrophy
- at 13 months, homozygotes show a 59% increase in heart weight-to-body weight ratio relative to wild-type mice

decreased body length
- nose to rump length less than controls at both 1 and 3 months

decreased body weight
- at 13 months, homozygotes show a 22% reduction in body weight relative to wild-type mice (34.5 ¿ 0.9 vs. 44.5 ¿ 1.1 g)

increased heart weight
- at 13 months, homozygotes show a 23% increase in heart weight relative to wild-type mice (186 ¿ 7.1 vs. 151 ¿ 2.5 mg)

increased spleen weight
- increased spleen weight while the thymus weight remains normal

increased susceptibility to weight gain
- body weight was less than controls at 3 months but identical at 8 months

hearing/vestibular/ear phenotype

abnormal basilar membrane morphology
- on an atherosclerotic diet, homozygotes display a sclerosed and atrophic basilar membrane

abnormal cochlea morphology
- endothelial nitric oxide synthase (eNOS) in mutant cochlea is distinctly reduced

abnormal stria vascularis morphology
- on an atherosclerotic diet, homozygotes display a sclerosed and atrophic stria vascularis

abnormal tectorial membrane morphology
- on an atherosclerotic diet, homozygotes display a sclerosed and atrophic tectorial membrane

cochlear inner hair cell degeneration
- at 24 weeks, homozygotes fed a normal diet show almost complete loss of IHCs in the basal turn and some IHC loss in the middle turn
- IHC loss at the base turn is exacerbated by an atherosclerotic diet

cochlear outer hair cell degeneration
- at 24 weeks, homozygotes fed a normal diet show almost complete loss of OHCs in the basal turn and some OHC loss in the middle turn
- OHC loss at the base turn is exacerbated by an atherosclerotic diet

deafness
- a high positive correlation between ABR thresholds at 16 and 8 kHz, or click and atherosclerotic lesions, and atherosclerotic plaque area of the aorta, and plasma total choelsterol levels is observed in both normal diet and high-fat diet homozygotes
- homozygotes fed a normal diet display hearing loss esp. at high frequencies as compared with C57BL/6J control mice

increased or absent threshold for auditory brainstem response
- at 10 weeks, homozygotes fed a normal diet display higher ABR thresholds than C57BL/6J control mice at all test frequencies, with more hearing loss noted at 32 kHz; by 24 weeks, further hearing loss is detected at all test stimuli levels
- homozygotes fed an atherosclerotic diet show higher ABR thresholds than homozygotes fed a normal diet

organ of Corti degeneration
- at 24 weeks, homozygotes fed a normal diet show significant degeneration of the organ of Corti in the basal turn while the middle turn is relatively normal
- degeneration of the organ of Corti is excerbated by an atherosclerotic diet, with complete loss noted in the basal turn in some animals

hematopoietic system phenotype

abnormal B cell activation
- spleen cells display polyclonal B cell activation, with increased expression of MHC II, Fas, and CD86 and lower expression of CD21, CD22, and CD23

abnormal CD4-positive, alpha beta T cell number
- clusters of CD4+ cells found in fatty streak lesions
- ratio of Th2 to Th1 cells is increased from 4.4 to 11.4 on a normal diet and up to 20.9 on a high cholesterol diet

abnormal T cell number
- increased numbers of cytokine producing T cells

decreased follicular B cell number
- decreased relative to controls

decreased hematocrit
- at 13 months, awake, unanesthetized homozygotes display slightly but significantly reduced hematocrits ( 11%) relative to wild-type mice at 41.7 ¿ 1.1% vs 46.6 ¿ 0.4%; in contrast, systolic blood pressures remain unaffected (140 ¿ 7.6 mmHg vs 136 ¿ 7.4 mmHg)
- Hg)

decreased marginal zone B cell number
- with induction of SLE by cGVH, levels are slightly decreased compared to wild-type

increased B cell number
- newly formed B cells are significantly increased compared to wild-type

increased IgM level
- IgM response to tetanus toxoid is significantly increased as compared to controls

increased immunoglobulin level
- mutants with cGVH-induced SLE show greatly increased levels compared to wild-type controls or untreated mutants

increased marginal zone B cell number
- increased 2-fold compared to wild-type

increased spleen weight
- increased spleen weight while the thymus weight remains normal

increased T-helper 2 cell number

homeostasis/metabolism phenotype

abnormal circulating cholesterol level
- decreased HDL/LDL ratio
- decreased HDL/total cholesterol ratio

abnormal enzyme/coenzyme activity
- activity of cholesterol synthesis enzyme HMG-CoA reductase is reduced up to 60% in aging mice compared to 30% in wild-type aging mice

decreased circulating glucose level

decreased circulating HDL cholesterol level

decreased circulating homocysteine level
- decrease in plasma total homocysteine levels

decreased circulating triglyceride level

glomerular capillary thrombosis
- lipid droplets filling glomerular capillary lumina at 36 weeks in about 50% of mice
- such thrombus-like structures commonly dsiplay a laminated appearance with adjacent foam cells in the mesangium

hyperlipidemia
- homozygotes develop hyperlipidemia; however, HDL cholesterol levels, body weight and blood glucose remain unchanged relative to C57BL/6J control mice on a normal diet, with no further differences noted on an atheroscletoric diet

increased cholesterol efflux
- in perhexiline-treated mice fed a high-fat diet

increased circulating cholesterol level
- 5 fold increase in total cholesterol at 24 and 36 weeks
- exercise (15 or 60 min/day swim) causes no significant changes in total cholesterol levels among homozygotes or wild-type mice relative to sedentary, genotype-matched controls
- increasing with age; 4-fold increase in plasma total cholesterol levels in 10-12 week old mutants and 13-fold increase at 29 weeks
- on a normal diet, homozygotes display significantly increased plasma total cholesterol (TC) levels relative to C57BL/6J control mice
- on an atherosclerotic diet, homozygotes show a further significant increase in plasma TC levels relative to homozygotes on a normal diet
- significantly increased relative to wild-type controls at 24 weeks of age; levels in mutants after induction of chronic graft versus host disease (cGVH) to induce systemic lupus erythematosus (SLE) are equivalent to the Apoe-null mice
- total serum cholesterol 20 fold higher than controls on high fat diet where controls show 4 fold increase over normal diet
- total serum cholesterol 70 fold higher than controls on a normal diet

increased circulating HDL cholesterol level
- in perhexiline-treated mice fed a high-fat diet

increased circulating LDL cholesterol level
- on a normal diet, homozygotes display significantly increased plasma LDL cholesterol levels relative to C57BL/6J control mice
- on an atherosclerotic diet, homozygotes show a further significant increase in plasma LDL levels relative to homozygotes on a normal diet

increased circulating triglyceride level
- 2-fold increase in plasma triglyceride levels in 10-12 week old mutants
- on a normal diet, homozygotes display significantly increased plasma triglyceride levels relative to C57BL/6J control mice
- on an atherosclerotic diet, homozygotes show a further significant increase in plasma triglyceride levels relative to homozygotes on a normal diet

increased circulating VLDL cholesterol level
- on a normal diet, homozygotes display significantly increased plasma VLDL cholesterol levels relative to C57BL/6J control mice
- on an atherosclerotic diet, homozygotes show a further significant increase in plasma VLDL cholesterol levels relative to homozygotes on a normal diet

xanthoma
- 1 of 11 aged mice on a normal diet develops cerebral xanthoma
- eruptive xanthomas on shoulder and back areas with lipids and extracellular matix as the predominant components

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
involves: 129P2/OlaHsd * C57BL/6

cardiovascular system phenotype

atherosclerotic lesions
- 75% of mice develop lesions in the aortic arch with most females and some males having calcification within the lesions
- aortic cartilaginous metaplasia is noted in the most severely affected mice
- extent of atherosclerosis correlates with plasma cholesterol levels
- fatty streaks with foam cells are found in the proximal aorta of 3-8 month old mice fed normal chow
- greater than in wild-type
- lesions get bigger with age and near total occlusion at the entrance of a coronary artery can be observed at 8 months of age
- mice exhibit atherosclerotic lesions in the aorta and aortic root
- the foam cells are often adjacent to valve attachment sites and can form multi-layers

immune system phenotype

lung inflammation
- isolated small foci of mononuclear cells are present in lung after 6 weeks of high-fat feeding

nervous system phenotype

abnormal astrocyte physiology
- astrocytes secrete less phospholipids or free cholesterol compared to wild-type astrocytes

abnormal synapse morphology
- cholesterol levels in the cytofacial leaflet are reduced
- elevated cholesterol in the exofacial leaflet of the synaptic plasma membrane but not so high as for Ldlr deficient mice

respiratory system phenotype

lung inflammation
- isolated small foci of mononuclear cells are present in lung after 6 weeks of high-fat feeding

homeostasis/metabolism phenotype

decreased circulating HDL cholesterol level
- mean HDL levels (33 mg/dl) are 45% of that found in controls

hyperlipidemia
- relative to wild-type

increased circulating cholesterol level
- mean total cholesterol levels are elevated about 5-fold over wild-type to 434 mg/dl
- plasma cholesterol levels increase significantly with time
- relative to wild-type
- total cholesterol levels are about 4-fold higher than controls with a mean of 379 mg/dl

increased circulating LDL cholesterol level
- mice have elevated levels of LDL in the blood

increased circulating triglyceride level
- circulating triglyceride levels are 123 mg/dl compared to 73 mg/dl in controls
- relative to wild-type

increased circulating VLDL cholesterol level
- the majority of lipoprotein particles in the blood are in the VLDL size range
- very high levels of VLDL cholesterol

increased prostaglandin level
- amount of PGE2 in aortas is 4X higher than in controls
- PGE2 level doubles on a high fat diet

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
either: B6.129P2-Apoe/J or (involves: 129P2/OlaHsd * C57BL/6J * ICR)

behavior/neurological phenotype

abnormal spatial learning
- 6-month old female mice show subtle learning impairment in water maze task compared to transgenic mutants; 6-month old males show significantly decreased learning ability in the Morris water maze test

decreased vertical activity
- mice have fewer rearing events and shorter rearing times than wild-type controls

mammalian phenotype

behavior/neurological phenotype
- Normal - no alterations in passive avoidance learning are observed; coordination levels measured in rotorod tests are similar to wild-type

nervous system phenotype
- mice exhibit age-dependent loss of synaptophysin-reactive terminals and microtubule-associated protein 2-positive neuronal dendrites in the neocortex and hippocampus
- Normal - mice exhibit age-dependent loss of synaptophysin-reactive terminals and microtubule-associated protein 2-positive neuronal dendrites in the neocortex and hippocampus, similar to wild-type
- mice show significant loss of synaptophysin-positive presynaptic terminals and neuronal dendrites of the neocortex and hippocampus with age (7-9 months compared to 3-4 months)
- Normal - mice show significant loss of synaptophysin-positive presynaptic terminals and neuronal dendrites of the neocortex and hippocampus with age (7-9 months compared to 3-4 months), similar to wild-type
- Normal - upon 18 mg/kg kainic acid injection, significant loss of neocortical synaptophysin-positive presynaptic terminals and disruption of hippocampal axons are observed, similar to wild-type

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
involves: 129P2/OlaHsd

behavior/neurological phenotype

increased anxiety-related response
- effect is age-dependent; phenotype is present in older mice, but not in young 2-4 month-old mice
- in the elevated-plus maze, mice show increased anxiety with reduced time and distance moved in the open arms; mice have significantly lower number of open-arm entries than wild-type

increased startle reflex
- response is higher in mice at 6 months of age compared to wild-type

muscle phenotype

decreased vasodilation
- impaired vasodilation induced by sodium nitroprusside 7 days after partial ligation of the left common carotid

nervous system phenotype

abnormal dendrite morphology
- mutants have lower levels of MAP 2-positive neuronal dendrites than wild-type; at 3 months, levels are similar in mutants and controls

decreased cerebral infarction size
- compared to in Tg(Eno2-APP751)10Cord Apoe^tm1Unc/Apoe^tm1Unc mice

cardiovascular system phenotype

altered susceptibility to atherosclerosis
- atherosclerotic lesion development is well advanced by 4-6 weeks after partial ligation of the left common carotid
- atherosclerotic lesions begin to form in the left common carotid by 2 weeks after partial ligation of the left common carotid

decreased vasodilation
- impaired vasodilation induced by sodium nitroprusside 7 days after partial ligation of the left common carotid

increased susceptibility to atherosclerosis
- bone marrow transplanted into Apoa1^tm1Unc homozygotes confer susceptibility to atherosclerosis

homeostasis/metabolism phenotype

abnormal circulating cholesterol level
- circulating VLDL/LDL cholesterol levels are increased compared to in Apobec1^tm1Chan homozygotes and wild-type mice

decreased cerebral infarction size
- compared to in Tg(Eno2-APP751)10Cord Apoe^tm1Unc/Apoe^tm1Unc mice

increased circulating cholesterol level
- when fed a chow or Western-type diet for 2 weeks, mice exhibit increased serum cholesterol compared with Apobec1^tm1Chan homozygotes and wild-type mice

increased circulating corticosterone level
- all males have higher plasma concentrations than wild-type after behavioral testing

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
B6.129P2-Apoe

adipose tissue phenotype

decreased brown adipose tissue mass
- decreased interscapular brown fat at 18 but not at 6 months

decreased epididymal fat pad weight
- epididymal white fat reduced at both 6 and 18 months

cardiovascular system phenotype

atherosclerotic lesions
- cellular composition of lesions is similar among Serpine1-deficient or transgenic, Apoe-deficient genotypes, or Apoe-deficient only mice; at early time points, a greater foam cell content is observed, with more prominent cholesterol clefts and necrotic areas evident with increasing age
- eas evident with increasing age

endocrine/exocrine gland phenotype

abnormal adrenal cortex morphology
- increased lipid droplets seen at six months

abnormal adrenal gland morphology

abnormal adrenal medulla morphology
- increased lipid droplets seen at six months

abnormal gland physiology

hypersecretion of corticosterone
- elevated adrenal levels at six months but not earlier
- fter 10 min of restraint stress plasma levels are elevated at six months but not at three months

hypopituitarism
- restraint stress at 6 months results in disproportionately low ACTH levels as compared to plasma corticosterone levels

hematopoietic system phenotype

increased CD4-positive, alpha beta T cell number
- mice maintained on a high fat diet and infected with Leishmania major generate more IL-4 and IL-5 producing CD4+ T cells compared to wild-type mice

homeostasis/metabolism phenotype

abnormal lipid level
- mice have increased levels of circulating oxidized lipids compared to wild-type mice

decreased circulating leptin level
- plasma leptin levels are low at both 6 and 18 months

increased circulating cholesterol level
- mice develop severe cholesterolemia when receiving a high fat diet from 6 to 30 weeks (elevated levels are detected at 6, 15, and 30 weeks)

behavior/neurological phenotype

abnormal kindling response
- after-discharge duration is significantly prolonged by the sixth trial
- delayed rekindling after 3-4 weeks

abnormal locomotor behavior
- mice spend more time than Tg(GFAP-APOE_i4)#Hol Apoe^tm1Unc/Apoe^tm1Unc in the center of an open field

abnormal response to new environment
- mice are less reluctant than wild-type mice to move into an open area
- mice consume food slower in a new environment than Tg(GFAP-APOE_i4)#Hol Apoe^tm1Unc/Apoe^tm1Unc and wild-type mice
- mice require more time to habituate to a novel environment compared to wild-type mice

abnormal spatial learning
- at 14 to 17 months of age, mice perform better than Tg(GFAP-APOE_i4)#Hol Apoe^tm1Unc/Apoe^tm1Unc and wild-type mice in a rotating holeboard test

abnormal thermal nociception
- 100% slower tail withdrawal latency
- 41% increase in foot withdrawal latency from painful thermal stimuli

decreased exploration in new environment
- exploratory behavior remains constant over several days whereas controls show higher initial exploratory behavior which drops off quickly
- reduced exploratory behavior in an open field test by 12 months although normal earlier

decreased startle reflex

increased anxiety-related response
- at 6 months as measured in an elevated plus maze

increased fluid intake
- increased water intake at 18 months

increased food intake
- increased food intake at 12 and 18 months but not earlier

immune system phenotype

abnormal cell-mediated immunity
- in an adoptive transfer experiment, the proliferation of Tg(TcrLCMV)2Aox CD45.2+ cell in mice fed a high fat diet and receiving then immunized with GP61-80 peptide with CpG is reduced compared to in wild-type mice similarly treated
- the immune response of mice fed a high fat diet to Leishmania major infection is skewed towards a Th2-type response

abnormal dendritic cell physiology
- CD8alpha-, but not CD8alpha+, dendritic cells are defective in their ability to produce IL-12p40
- dendrictic cells mount reduced IL-12p40 and TNF-alpha responses to stimulation with zymosan, poly(I:C), LPS, imiquimod, and a combination of anti-CD40 antibodies and CpG compared to wild-type mice but similar to wild-type mice fed a high fat diet
- dendritic cells from mice on a high fat diet are severely impaired in their ability to produce Il-12p40, -12p70, -6, and TNF-alpha compared to dendritic cells from wild-type mice on a high fat diet
- Normal - however, CD8alpha+ dendritic cells produce normal amounts of Il-12p70 and -12p40
- Normal - however, the immune responses of bone marrow derived dendritic cells from mice fed a high fat diet or splenic dendritic cells from mice fed a regular diet are normal
- in mice fed a high fat diet, dendritic cell production of IL-12p40, IL-6 and TNF-alpha after 35 to 40 weeks, but not after 6 to 10 weeks, is severely impaired compared to wild-type cells in response to CpG/anti-CD-40 stimulation
- mice fed a high fat diet and co-stimulated with CpG or LPS have fewer IL-12p40-producing CD8alpha- dendritic cells (4.6+/-1.1%) than wild-type mice fed a high fat diet (15.3+/-2.4%)

increased CD4-positive, alpha beta T cell number
- mice maintained on a high fat diet and infected with Leishmania major generate more IL-4 and IL-5 producing CD4+ T cells compared to wild-type mice

increased susceptibility to parasitic infection
- mice maintained on a high fat diet and infected with Leishmania major produce more IL-4 and IL-5 producing CD4+ T cells compared to wild-type mice
- mice maintained on a high fat diet or regular chow and infected with Leishmania major exhibit an increased swelling and parasitic burden at the site of infection (footpad)
- the immune response of mice fed a high fat diet to Leishmania major infection is skewed towards a Th2-type response

integument phenotype

abnormal thermal nociception
- 100% slower tail withdrawal latency
- 41% increase in foot withdrawal latency from painful thermal stimuli

nervous system phenotype

abnormal kindling response
- after-discharge duration is significantly prolonged by the sixth trial
- delayed rekindling after 3-4 weeks

abnormal myelin sheath morphology
- blurring of lipid membrane border between axons and Schwann cells
- very little Schwann cell cytoplasm

abnormal sciatic nerve morphology
- blurring of lipid membrane border between axons and Schwann cells
- cross-section of unmyelinated axons is irregular
- ratio of unmyelinated to myelinated axons is reduced
- reduced number of unmyelinated axons
- very little Schwann cell cytoplasm

abnormal synaptic vesicle morphology
- synaptophysin levels are somewhat more reduced than in controls after entorhinal cortex lesion

hypopituitarism
- restraint stress at 6 months results in disproportionately low ACTH levels as compared to plasma corticosterone levels

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6

cardiovascular system phenotype

atherosclerotic lesions
- most severe in the aortic arch region

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
involves: 129P2/OlaHsd * C57BL/6 * FVB/N

cardiovascular system phenotype

atherosclerotic lesions
- lesions are observed in aortas of nontransgenic mice

Genotype: Apoe^tm1Unc/Apoe⁺
involves: 129P2/OlaHsd * C57BL/6

homeostasis/metabolism phenotype

increased circulating triglyceride level
- circulating triglyceride levels are 39% higher than in wild-type controls

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
involves: 129P2/OlaHsd * C57BL/6 * DBA

homeostasis/metabolism phenotype

abnormal cholesterol homeostasis
- increase in the APOB lipoprotein cholesterol level compared to wild-type controls
- the ratio of saturated + monounsaturated/polyunsaturated cholesterol ester fatty acid species in the LDL fraction is significantly increased compared to Ldlr^tm1Her single mutants
- there is a 2.3 fold increase in the ratio of saturated + monounsaturated/polyunsaturated cholesterol ester fatty acid species compared to Ldlr^tm1Her single mutants
- ts

abnormal circulating protein level
- increase in APOB-48

abnormal lipid homeostasis
- the HDL phospholipid fraction is enriched in 16:0 and 18:0 species and contains less 20:4 and 22:6 species compared to Ldlr^tm1Her single mutants

decreased circulating HDL cholesterol level
- about a 50% decrease in HDL compared to controls

increased circulating cholesterol level
- increased total cholesterol and esterfied cholesterol levels in the plasma

increased circulating phospholipid level

References

Piedrahita JA; Zhang SH; Hagaman JR; Oliver PM; Maeda N. 1992. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc Natl Acad Sci U S A 89(10):4471-5PubMed: 1584779 MGI: J:1050

Additional - Apoe^tm1Unc related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Apoe
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, these mice can be bred as homozygotes.
- Additional Breeding and Husbandry Support
Citation
When using the D2.129P2(B6)-Apoe^tm1Unc/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #007067 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

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Cryorecovery - Pricing

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	Heterozygous for Apoe<tm1Unc>

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Frozen Mouse Embryo	D2.129P2(B6)-Apoe<tm1Unc>/J	$2595.00
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Frozen Mouse Embryo	D2.129P2(B6)-Apoe<tm1Unc>/J	$3373.50
Frozen Mouse Embryo	D2.129P2(B6)-Apoe<tm1Unc>/J	$3373.50

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Donating Investigator

Genetic overview

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Detailed Description

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Additional Information

Selected References

Apoetm1Unc

Allele Symbol: Apoetm1Unc

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Apoetm1Unc related

Mammalian Phenotype Terms by Genotype

Genotype: Apoetm1Unc/Apoetm1UncB6.129P2-Apoe/J

behavior/neurological phenotype

immune system phenotype

integument phenotype

liver/biliary system phenotype

mortality/aging

muscle phenotype

nervous system phenotype

renal/urinary system phenotype

respiratory system phenotype

skeleton phenotype

taste/olfaction phenotype

vision/eye phenotype

cardiovascular system phenotype

cellular phenotype

growth/size/body region phenotype

hearing/vestibular/ear phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

Genotype: Apoetm1Unc/Apoetm1Uncinvolves: 129P2/OlaHsd * C57BL/6

cardiovascular system phenotype

immune system phenotype

nervous system phenotype

respiratory system phenotype

homeostasis/metabolism phenotype

Genotype: Apoetm1Unc/Apoetm1Unceither: B6.129P2-Apoe/J or (involves: 129P2/OlaHsd * C57BL/6J * ICR)

behavior/neurological phenotype

mammalian phenotype

Genotype: Apoetm1Unc/Apoetm1Uncinvolves: 129P2/OlaHsd

behavior/neurological phenotype

muscle phenotype

nervous system phenotype

cardiovascular system phenotype

homeostasis/metabolism phenotype

Genotype: Apoetm1Unc/Apoetm1UncB6.129P2-Apoe

adipose tissue phenotype

cardiovascular system phenotype

endocrine/exocrine gland phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

behavior/neurological phenotype

immune system phenotype

integument phenotype

nervous system phenotype

Genotype: Apoetm1Unc/Apoetm1Uncinvolves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6

cardiovascular system phenotype

Genotype: Apoetm1Unc/Apoetm1Uncinvolves: 129P2/OlaHsd * C57BL/6 * FVB/N

cardiovascular system phenotype

Genotype: Apoetm1Unc/Apoe+involves: 129P2/OlaHsd * C57BL/6

homeostasis/metabolism phenotype

Genotype: Apoetm1Unc/Apoetm1Uncinvolves: 129P2/OlaHsd * C57BL/6 * DBA

homeostasis/metabolism phenotype

References

Additional - Apoetm1Unc related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Apoe^tm1Unc

Allele Symbol: Apoe^tm1Unc

Genotype: Apoe^tm1Unc related

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
B6.129P2-Apoe/J

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
involves: 129P2/OlaHsd * C57BL/6

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
either: B6.129P2-Apoe/J or (involves: 129P2/OlaHsd * C57BL/6J * ICR)

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
involves: 129P2/OlaHsd

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
B6.129P2-Apoe

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
involves: 129P2/OlaHsd * C57BL/6 * FVB/N

Genotype: Apoe^tm1Unc/Apoe⁺
involves: 129P2/OlaHsd * C57BL/6

Genotype: Apoe^tm1Unc/Apoe^tm1Unc
involves: 129P2/OlaHsd * C57BL/6 * DBA

Additional - Apoe^tm1Unc related