Mouse Genome Informatics
cx1
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-MAPT*P301L)#Kha/0

involves: 129/Sv * C57BL/6 * CBA * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• progressive atrophy of dentate granule cells
• progressive atrophy of hippocampal pyramidal neurons


Mouse Genome Informatics
cx2
    Tg(Camk2a-tTA)1Mmay/?
Tg(tetO-MAPT*P301L)#Kha/?

involves: 129S6/SvEvTac * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• a significant loss in brain weight by 5.5 months
• when treated with doxycycline during 5.5 to 10 months, the loss of brain weight was significantly protected
• significant decrease in total numbers of CA1 hippocampal neurons
• CA1 neuron estimates were stabilized after brief (6- to 8-week) doxycycline treatment
• gross atrophy of the forebrain was evident in a 10-month-old mouse
• develop argyrophilic tangle-like inclusions in the cortex by 4 months and in the hippocampal formation by 5.5 months
• when treated with doxycycline at 2.5 month, the tau pathology ceased to progress
• the neuronal inclusions composed of a mass of straight tau filaments
• when treated with doxycycline at 2.5 month, the tau pathology ceased to progress
• approximately 23% of CA1 pyramidal cells remaining at 8.5 months
• CA1 neuron estimates were stabilized after brief (6- to 8-week) doxycycline treatment

behavior/neurological
• he retention of spatial memory examined by the Morris water maze were impaired as the mice aged
• deficit in spatial navigation was also seen in younger mice
• the performance improved when treated with doxycycline at 2.5 month-old or at 5.5 month-old

Mouse Models of Human Disease
OMIM IDRef(s)
Alzheimer Disease; AD 104300 J:99626


Mouse Genome Informatics
cx3
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-MAPT*P301L)#Kha/0

involves: 129S6/SvEvTac * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• amount of time spent in open arms of elevated plus maze is increased relative to nontransgenic mice at 6 and 10 months of age, but not 2 months
• higher ratio of time spent in open not closed arms relative to nontransgenic mice at 10 months of age, but not 2 or 6 months
• exploration of light chamber is increased relative to nontransgenic mice at 6 months of age, but not 2 or 10 months
• higher ratio of time spent in light not dark relative to nontransgenic miceat 10 months of age, but not 2 or 6 months
• decreased tendency to explore the center of the open field relative to nontransgenic mice
• progressive decrease in percent of time spent freezing in response to unconditioned stimulus beginning at 2 months of age
• progressive decrease in percent of time spent freezing in response to conditioned stimulus beginning at 6 months of age
• mice exhibit progressive hyperactivity in open field analysis and elevated plus maze
• total distance travelled in open field assay is increased relative to nontransgenic mice at 6 and 10 months of age, but not 2 months
• average speed is increased relative to nontransgenic mice at 6 and 10 months of age, but not 2 months
• total time spent immobile is increased relative to nontransgenic mice at 6 and 10 months of age, but not 2 months

nervous system
• neurofibrilliary tangles are observed by immunostaining in the CA1 region of the hippocampus beginning at 6 months of age and progressing to an extensive pathology by 11 months of age
• neurofibrilliary tangles are observed by immunostaining in the amygdala beginning at 2 months of age and progressing to an extensive pathology by 10 months of age
• tau burden increases with age in the amygdala and CA1 region of the hippocampus

Mouse Models of Human Disease
OMIM IDRef(s)
Frontotemporal Dementia; FTD 600274 J:207366


Mouse Genome Informatics
cx4
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-MAPT*P301L)#Kha/0

involves: FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• reduction in exploration in open-field tests
• mutants first exhibit impaired spatial reference memory at 2.5 months of age, showing a slightly reduced search bias for the target quadrant than controls in the Morris water maze
• spatial memory retention becomes more impaired with age, especially after 4 months of age, with the mean probe performance being equal to random swimming, indicating little or no retention of spatial memory
• mutants exhibit cognitive impairments in the acquisition phases of the Morris water maze, showing a longer mean distance to locate the hidden platform
• clasping and limb retraction when lifted by the tail
• mutants exhibit longer latencies to traverse a beam
• mutants develop an age-dependent increase in the time taken to start swimming, however they are able to achieve comparable mean swim speeds during probe trials
• from about 9.5 months of age, the most severely affected mutants develop hunched posture with hindlimb dysfunction and tail rigor
• develop dystonic posture with tail rigor at 9.5 months of age
• from about 9.5 months of age, the most severely affected mutants exhibit decreased ambulation

growth/size
• from about 9.5 months of age, the most severely affected mutants exhibit decreased body weight

nervous system
• 4-7% reduction in brain weight at 4 months of age
• atrophy of the forebrain is seen by 5 months of age
• age-dependent progression of tau processing that results in pathophysiological deposition of tau as mature tangles in the brain
• mutants exhibit age-dependent progression of neurofibrillary tangle formation, with tangles first appearing in the neocortex and then progressing into the hippocampus and limbic structures with increasing age
• neurofibrillary tangles develop in the hippocampus in a distinct pattern; mature tangles occur initially in CA1 pyramidal neurons, spread to CA2, and by 8.5 months of age include pyramidal neurons in CA2 and granular neurons of the dentate gyrus
• abnormal conformations of tau are present in the hippocampus and neocortex of 2.5-month old mutants
• reactive astrocytes in forebrains of 10 month old mutants
• atrophy of the dorsal corticospinal tracts accompanied by loss of neurofilament
• degeneration in the hippocampus and neocortex is seen in 10 month old mutants
• massive neuronal loss, most apparent in the CA1 region of the hippocampus
• spinal cords appear thinner, however, no decrease in motor neuron density is seen

muscle
• develop dystonic posture with tail rigor at 9.5 months of age