Phenotypes associated with this allele

• Allele Symbol: Tg(Prnp-MAPT*P301S)PS19Vle
• Allele Name: transgene insertion PS19, Virginia M Y Lee
• Allele ID: MGI:3768407
• Summary: 7 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cx1	Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/0 Tg(Prnp-MAPT*P301S)PS19Vle/0	B6.Cg-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas Tg(Prnp-MAPT*P301S)PS19Vle	MGI:5629689
cx2	Tg(APPV717F)109Ili/0 Tg(Prnp-MAPT*P301S)PS19Vle/0	involves: C3H * C57BL/6	MGI:5512698
cx3	Syngr3^em1Pave/Syngr3^+ Tg(Prnp-MAPT*P301S)PS19Vle/0	involves: C3H * C57BL/6	MGI:6690265
cx4	Nos1ap^tm1Tsso/Nos1ap^tm1Tsso Tg(Prnp-MAPT*P301S)PS19Vle/0	involves: C57BL/6 * C3H	MGI:6414672
tg5	Tg(Prnp-MAPT*P301S)PS19Vle/Tg(Prnp-MAPT*P301S)PS19Vle	involves: C3H * C57BL/6	MGI:3768517
tg6	Tg(Prnp-MAPT*P301S)PS19Vle/0	B6.Cg-Tg(Prnp-MAPT*P301S)PS19Vle	MGI:5512699
tg7	Tg(Prnp-MAPT*P301S)PS19Vle/0	involves: C3H * C57BL/6	MGI:3768518

Genotype
MGI:5629689

cx1

• Allelic Composition: Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/0; Tg(Prnp-MAPT*P301S)PS19Vle/0
• Genetic Background: B6.Cg-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas Tg(Prnp-MAPT*P301S)PS19Vle

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

homeostasis/metabolism

amyloid beta deposits ( J:211723 )

• mice develop extracellular amyloid plaque to a similar extent as mice expressing only the Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas trasngene

nervous system

amyloid beta deposits ( J:211723 )

• mice develop extracellular amyloid plaque to a similar extent as mice expressing only the Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas trasngene

abnormal hippocampus morphology ( J:211723 )

• mice show aggravation of hyperphosphorylated tau pathology that is already seen at 3 months of age

abnormal hippocampal mossy fiber morphology ( J:211723 )

• mossy fiber degeneration by 9 months of age

hippocampal neuron degeneration ( J:211723 )

loss of hippocampal neurons ( J:211723 )

• mice show reduced number of CA1 neurons at 9 months of age compared to either single mutant, indicating increased loss of hippocampal CA1 neurons

hippocampus atrophy ( J:211723 )

• hippocampal atrophy in aged mice

astrocytosis ( J:211723 )

• mice show increased astrocytosis in the cortex and thalamus at 3 months of age, and by 9 months of age, astrocytosis is strongly elevated in the hippocampus

abnormal dendrite morphology ( J:211723 )

• aged mice show a decrease in apical dendrite density in the hippocampal stratum radiatum

abnormal synapse morphology ( J:211723 )

• increase in loss of synapses

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Alzheimer's disease		DOID:10652		J:211723

Genotype
MGI:5512698

cx2

• Allelic Composition: Tg(APPV717F)109Ili/0; Tg(Prnp-MAPT*P301S)PS19Vle/0
• Genetic Background: involves: C3H * C57BL/6

mortality/aging

premature death ( J:165441 )

• median survival of females and males is 12 and 10 months of age, respectively

• mutants exhibit a greater acceleration of death than single Tg(Prnp-MAPT*P301S)PS19Vle mice

growth/size/body

weight loss ( J:165441 )

• decrease in weight with increasing age

• males show a greater decrease in percentage of body weight than females

• mutants exhibit a greater acceleration weight loss than single Tg(Prnp-MAPT*P301S)PS19Vle mice

behavior/neurological

paralysis ( J:165441 )

• 56% of mutants exhibit paresis or paralysis and presence of a hunchback posture at 11 months of age

• males show a more profound motor phenotype than females

• mutants exhibit a greater acceleration of motor phenotype than single Tg(Prnp-MAPT*P301S)PS19Vle mice

paresis ( J:165441 )

• 56% of mutants exhibit paresis or paralysis and presence of a hunchback posture at 11 months of age

nervous system

amyloid beta deposits ( J:165441 )

• limited amyloid beta deposits are seen at 8 months of age within the corpus callosum, stratum oriens, and radiatum of CA1, visual cortex, molecular layer of the dentate gyrus, and retrosplenial area

• at 11 months of age, an increase in amyloid beta deposition is seen in the same areas as at 8 months of age

• mutants exhibit an increase in plaque load with increasing age from 8 to 11 months of age for the anterior and posterior hippocampus

• most amyloid beta deposits are not composed of amyloid beta species that are assembled into ThS-positive amyloid fibrils

neurofibrillary tangles ( J:165441 )

• mutants develop ThS-positive neurofibrillary tangles at a much earlier age than single Tg(Prnp-MAPT*P301S)PS19Vle mice

• a greater proportion of double mutants develop tangles at 8 and 11 months of age than single Tg(Prnp-MAPT*P301S)PS19Vle mice

tau protein deposits ( J:165441 )

• mutants exhibit an accelerated progression in the distribution of abnormally phosphorylated tau from the entorhinal and neocortex, followed by involvement of the hippocampal formation and subcortical structures, to finally penetration of all layers of the neocortex compared to single Tg(Prnp-MAPT*P301S)PS19Vle mice

neurodegeneration ( J:165441 )

• substantial loss of neurons that secrete amyloid beta

skeleton

kyphosis ( J:165441 )

• 56% of mutants exhibit paresis or paralysis and presence of a hunchback posture at 11 months of age

homeostasis/metabolism

amyloid beta deposits ( J:165441 )

• limited amyloid beta deposits are seen at 8 months of age within the corpus callosum, stratum oriens, and radiatum of CA1, visual cortex, molecular layer of the dentate gyrus, and retrosplenial area

• at 11 months of age, an increase in amyloid beta deposition is seen in the same areas as at 8 months of age

• mutants exhibit an increase in plaque load with increasing age from 8 to 11 months of age for the anterior and posterior hippocampus

• most amyloid beta deposits are not composed of amyloid beta species that are assembled into ThS-positive amyloid fibrils

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Alzheimer's disease		DOID:10652		J:165441

Genotype
MGI:6690265

cx3

• Allelic Composition: Syngr3^em1Pave/Syngr3⁺; Tg(Prnp-MAPT*P301S)PS19Vle/0
• Genetic Background: involves: C3H * C57BL/6

behavior/neurological

behavior/neurological phenotype ( J:303506 )

N • normal working memory as evidenced by performance in Morris water maze test at age 6-7 months

hematopoietic system

microgliosis ( J:303506 )

• increased number of activated microglia in stratum lucidum

immune system

microgliosis ( J:303506 )

• increased number of activated microglia in stratum lucidum

nervous system

nervous system phenotype ( J:303506 )

N • normal long-term potentiation response to three-theta-burst-stimulation (TBS) in mossy fiber CA3 synapses at age 6-7 months

N • normal long-term potentiation response in Schaffer collateral CA1 synapses at age 8 months

N • no loss of synapses in synaptic stratum lucidum area at age 8-9 months

N • normal number of mossy fiber boutons at age 8-9 months

microgliosis ( J:303506 )

• increased number of activated microglia in stratum lucidum

astrocytosis ( J:303506 )

• increased number of reactive astrocytes in stratum lucidum

Genotype
MGI:6414672

cx4

• Allelic Composition: Nos1ap^tm1Tsso/Nos1ap^tm1Tsso; Tg(Prnp-MAPT*P301S)PS19Vle/0
• Genetic Background: involves: C57BL/6 * C3H

nervous system

nervous system phenotype ( J:278451 )

N • mice show reduced levels of total and phosphorylated tau and a reduction of Sarkosyl-insoluble tau indicating reduced tau pathology and ameliorated brain atrophy and neuron loss

Genotype
MGI:3768517

tg5

• Allelic Composition: Tg(Prnp-MAPT*P301S)PS19Vle/Tg(Prnp-MAPT*P301S)PS19Vle
• Genetic Background: involves: C3H * C57BL/6

behavior/neurological

abnormal sexual interaction ( J:119741 )

♀ • homozygous females do not mate, so mice have to be maintained as hemizygotes

Genotype
MGI:5512699

tg6

• Allelic Composition: Tg(Prnp-MAPT*P301S)PS19Vle/0
• Genetic Background: B6.Cg-Tg(Prnp-MAPT*P301S)PS19Vle

behavior/neurological

abnormal behavior ( J:174441 )

♂ • in the Y-maze test, the total percentage of alternations is decreased indicating impaired spontaneous alternation

♂ • in the Barnes circular maze test, males are able to locate the correct target hole where the escape box had been in the probe trial, however they spend less time around the target hole than wild-type mice

abnormal contextual conditioning behavior ( J:174441 )

♂ • in the contextual fear conditioning test, mutants show decreased immobility in the fourth time point only

abnormal emotion/affect behavior ( J:174441 )

♂ • in a portion of the Porsolt forced swim test, mutants show decreased immobility time and increased distance traveled, suggesting that despair-like behavior might be decreased, however, generally over the entire test, no statistical significance is seen for immobility

decreased anxiety-related response ( J:174441 )

♂ • in the elevated plus-maze test, entries into and time spent on the open arms is increased and in the open field test, time spent in the center of the field is increased, indicating decreased anxiety-like behavior

increased vertical activity ( J:174441 )

♂ • vertical activity of 14 week old males is increased in the latter half of the open field test

increased locomotor activity ( J:174441 , J:174441 )

• in the open field test, 14 week old males show an increase in total locomotive distance (J:174441)

♂ • in the open field test, 14 week old males show an increase in total locomotive distance and an increase in stereotypic locomotion (J:174441)

♂ • in the Y-maze test, males show increased numbers of entries into each arm, total alternations, and total distance traveled indicating hyperactivity (J:174441)

decreased thermal nociceptive threshold ( J:174441 )

♂ • males exhibit decreased thresholds in the hot plate test, indicating increased antinociceptive responses

abnormal social investigation ( J:174441 )

♂ • in Crawley's three-chamber social approach test, males spend a shorter time with stranger mice than with familiar mice compared to wild-type mice which spend more time with stranger mice, indicating some impaired sociability or object recognition memory

♂ • however, no differences were seen in the social interaction test of a one-chamber novel environment

nervous system

tau protein deposits ( J:174441 )

♂ • hyperphosphorylated tau protein accumulation is seen in the lateral globus pallidus, amygdala, auditory cortex, ventral hippocampus, the cingulate cortex, anterior cortical amygdaloid nucleus, and dorsal hippocampus at 4 months of age

increased prepulse inhibition ( J:174441 )

♂ • males younger than 6 months of age exhibit lower startle amplitudes than wild-type mice at 110 dB and 120 dB and an increase in percent prepulse inhibition

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Alzheimer's disease		DOID:10652		J:174441

Genotype
MGI:3768518

tg7

• Allelic Composition: Tg(Prnp-MAPT*P301S)PS19Vle/0
• Genetic Background: involves: C3H * C57BL/6

mortality/aging

premature death ( J:119741 , J:165441 )

• ~80% of mice die by 12 months of age, with median survival of ~9 months (J:119741)

behavior/neurological

abnormal spatial learning ( J:174441 )

♀ • 6 month old females are able to learn to locate the platform of the Morris water maze during training and latencies to find the visible platform are similar between mutants and wild-type mice, however mutants spend more time in finding the invisible platform, indicating impaired spatial learning ability

♀ • during the probe trail of the Morris water maze, mutant females show less time and path length in the pool quadrant where the platform had previously been placed and a smaller number of target platform crossings

limb grasping ( J:119741 )

• at 3 months of age, mice exhibit limb grasping and limb retraction when lifted by the tail, whereas mice expressing a wild-type MAPT transgene show no neurodegenerative phenotype up to 24 months of age

weakness ( J:119741 )

• limb grasping at 3 months of age is followed by limb weakness

hunched posture ( J:119741 , J:165441 )

• paralysis is associated with hunched-back posture (J:119741)

paralysis ( J:119741 , J:165441 )

• mice show paralysis at 7-10 months of age (J:119741)

• 44% of mutants exhibit paresis or paralysis and presence of a hunchback posture at 11 months of age (J:165441)

paresis ( J:165441 )

• 44% of mutants exhibit paresis or paralysis and presence of a hunchback posture at 11 months of age

nervous system

dilated brain ventricle ( J:119741 )

• by 8 months of age, ventricular dilatation is seen

abnormal amygdala morphology ( J:119741 )

• neuron loss is observed at 12 months of age

abnormal entorhinal cortex morphology ( J:119741 )

• neuron loss is observed at 12 months of age

abnormal dentate gyrus morphology ( J:119741 )

• at 3 months, mice have neurofilament light chain and tau-positive spheroids in the dentate gyrus, as well as in the cortex

abnormal hippocampal mossy fiber morphology ( J:119741 )

• at 3 months but not at 6 months, neurofilament light chain-positive mossy fibers are not detected in CA3 of hippocampus at 3 months but not at 6 months, neurofilament light chain-positive mossy fibers are not detected in CA3 of hippocampus

abnormal hippocampus pyramidal cell morphology ( J:119741 )

• significant reduction in number in the hippocampal CA3 region is found at 12 months of age, but no loss is detected at 6 months

loss of hippocampal neurons ( J:119741 )

• up to 6 months, mice show no neuron loss, but by 8 months of age, neuron loss in the hippocampus is seen, becoming more severe in hippocampus, as well as amygdala, neocortex and entorhinal cortex by 12 months of age

decreased hippocampus volume ( J:119741 )

• ~25% and ~40% reductions in hippocampal volume at 9 and 12 months of age respectively

hippocampus atrophy ( J:119741 )

• marked hippocampal atrophy at 9 months of age

abnormal cerebral cortex morphology ( J:119741 )

• at 3 months, mice have neurofilament light chain and tau-positive spheroids in the cerebral cortex

• prominent atrophy of neocortex is observed at 9 months of age, with a 20% reduction in volume at 12 months of age

brain atrophy ( J:119741 )

• limb grasping at 3 months of age is followed by brain atrophy

neurofibrillary tangles ( J:119741 , J:165441 )

• at 6 months of age, neurofibrillary tangles (NFT) are evident in neocortex, amygdala, hippocampus, brain stem and spinal cord but none are found in mice expressing wild-type human MAPT up to 24 months of age (J:119741)

• mutants develop ThS-positive neurofibrillary tangles (J:165441)

tau protein deposits ( J:119741 , J:165441 , J:233816 )

• with aging, brains of mice have increasing levels of insoluble tau deposits composed mainly of transgenic human tau; decrease in solubility of tau is observed between 3 and 6 months (J:119741)

• at 3 months of age, mutants and mice expressing wild-type transgenic human tau show weak perikaryal and dendritic tau staining mainly in hippocampus, amygdala, cortex, brain stem, and spinal cord; at 6 months, mutants show stronger tau-positive neuronal staining in the hippocampus, amygdala, and spinal cord but older mice expressing wild-type human tau protein show no increases up to 12 months (J:119741)

• mutants exhibit progression in the distribution of abnormally phosphorylated tau from the entorhinal and neocortex, followed by involvement of the hippocampal formation and subcortical structures, to finally penetration of all layers of the neocortex (J:165441)

• aggregation of insoluble tau in the cortex and hippocampus (J:233816)

astrocytosis ( J:119741 )

• microglial activation precedes astrogliosis in brain regions containing NFTs; this is found in the brain and spinal cord, especially in white matter at 3 months of age with increases seen at 6 months in white and gray matter of hippocampus, amygdala, entorhinal cortex and spinal cord

• gliosis is striking at 6 months in the white matter where little tau pathology exists

• younger mice (3-4 months) show no overt gliosis but increased microglial activation is detected in the hippocampus

abnormal spinal cord white matter morphology ( J:119741 )

• at 3 months, mice have neurofilament light chain and tau-positive spheroids in the spinal cord white matter

neurodegeneration ( J:119741 )

• mice show progressive neurodegeneration starting at 1 month of age, as determined by increasing loss of synaptophysin immunoreactivity

hippocampal neuron degeneration ( J:119741 )

abnormal CNS synaptic transmission ( J:119741 )

• basal synaptic transmission is impaired at 6 months

• mice show small fiber volley amplitude, fEPSP slopes and amplitudes at all stimulus intensities tested

abnormal excitatory postsynaptic potential ( J:119741 )

• at 6 months, the maximum fEPSP is reduced relative to wild-type MAPT transgenic mice

reduced long-term potentiation ( J:119741 )

• LTP in CA1 region of hippocampus is significantly deteriorated, indicating attenuated postsynaptic responsiveness and compromised synaptic plasticity, but at 6 months no overt reduction in neuron number is detected

decreased paired-pulse facilitation ( J:119741 )

• at 6 months, mice show significantly reduce paired pulse facilitation (PPF) ratio at all stimulus intervals

muscle

dystrophic muscle ( J:119741 )

• affected muscles show group atrophies with small angular fibers, indicating chronic denervation of motor neurons

progressive muscle weakness ( J:119741 )

• mice show motor increasing weakness and neurogenic muscular atrophy after 3 months of age

growth/size/body

weight loss ( J:165441 )

• slight decrease in weight is seen at 11 months of age