Phenotypes Associated with This Genotype

Genotype
MGI:3768518

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

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

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