Mouse Genome Informatics
cx1
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-APPSwInd)107Dbo/0

(FVB/NJ x B6.Cg-Tg(tetO-APPSwInd)107Dbo Tg(Camk2a-tTA)1Mmay)F1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
N
• bitransgenic (off-DOX) males perform like wild-type males in Plus water maze apparatus, swimming abilities, and latency to find platform (J:195259)
• in a test of long-term reference memory, radial arm water maze (RAWM) administered after a 24 hour delay, bi-transgenic males (off-DOX) performed at the level of chance with a significantly increased number of errors compared to wild type (J:195259)
• bi-transgenic mice (on-DOX) perform similar to non-transgenic controls in RAWM (J:195259)
• in a test of cognitive flexibility, as assessed by changing the water maze escape platform position daily, bi-transgenic males (on-DOX) continue to visit the original location significantly more frequently than non-transgenic controls, however, in subsequent sessions the error rate becomes similar to non-transgenic controls (J:195259)
• 12.5 month old bi-transgenic males (off-DOX) exhibit significantly less preference for exploring the new arm of the two trial Y maze (a test of short term spatial memory) (J:195259)
• 12.5 month old bi-transgenic males (on-DOX) exhibit a preference for the new arm (J:195259)
• 12.5 month old bi-transgenic males (off-DOX) exhibit improved performance after successive trials, but an increased number of errors compared to wild-type non-Tg and on-DOX Tg controls in the radial arm water maze (RAWM), a test of long term spatial memory (J:195259)

nervous system
• found in the CA layer of the hippocampus in off-DOX and on-DOX (for 7 days) 23 month old bi-transgenic males, however, after 5 weeks on doxycycline APP/amyloid beta (as assessed by mAb 6E10) immunoreactivity disappears (J:195259)
• a low level of mobile, water-extractable Abeta42 is present in bitransgenic males treated with DOX for up to 4 weeks (J:195259)

homeostasis/metabolism
• found in the CA layer of the hippocampus in off-DOX and on-DOX (for 7 days) 23 month old bi-transgenic males, however, after 5 weeks on doxycycline APP/amyloid beta (as assessed by mAb 6E10) immunoreactivity disappears (J:195259)
• a low level of mobile, water-extractable Abeta42 is present in bitransgenic males treated with DOX for up to 4 weeks (J:195259)


Mouse Genome Informatics
cx2
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-APPSwInd)107Dbo/0

involves: C3H/HeJ * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• doxycycline-mediated suppression of transgenic APPSwInd synthesis leads to parallel reductions of amyloid beta peptide levels
• early onset amyloid formation is observed, with plaques observed as early as 8 weeks of age in mice receiving no doxycycline (DOX) treatment
• plaques are restricted to the forebrain, including the cortex, hippocampus, olfactory bulb, and striatum; by 6 months, amyloid burden covers large cortical and hippocampal areas
• first observed plaques are fibrillar-core deposits; in 6 month old animals, diffuse plaques are apparent and these are abundant at 9 months, while in 9-12 month-old mice, plaques are visible in the thalamus
• no lesions are observed in the cerebellum or brain stem
• animals receiving no treatment display moderate amyloid pathology at 6 months, which progresses to a severe amyloid burden by 9 months
• mice raised for 6 months with no (DOX) treatment, followed by 3 or 6 months of DOX treatment show similar pathology to untreated 6-month old animals, despite relatively long lesion clearance times
• mice exhibit a progressive neuronal atrophy that is most pronounced in the granule cell layer of hippocampal dentate gyrus
• mice exhibit a progressive neuronal atrophy that is most pronounced in the granule cell layer of hippocampal dentate gyrus
• however, when mice are reared on doxycycline, cell loss is not observed
• first visible plaques are fibrillary-cored deposits
• activated astrocytes are found near plaques in all affected mice glial pathology is more severe in older mice
• if transgene expression is suppressed with doxycycline treatment, pathology does not progress in severity
• mice produce transgenic APP protein at 10- to 30-fold over endogenous App levels
• sensitivity of transgene suppression by doxycycline is intermediate between mice of line 885 and line 102
• neuritic pathology is observed around plaques; neuritic pathology is more severe in older mice
• if transgene expression is suppressed with doxycycline treatment, pathology does not progress in severity

behavior/neurological
• all animals raised with doxycycline have altered circadian rhythms with less distinction between day- and nighttime activity levels
• hyperactive behavior is partially reversed in some mice by 1 month of transgene suppression starting at 4-5 months of age
• untreated mice show hyperactivity, often running in circles around the perimeter of cages
• similar patterns of activity are observed in Morris water maze, with repetitive swim patterns seen in radial water maze swim test
• hyperactive phenotype penetrance is ~100%
• untreated mice show 10-fold more ambulatory activity during the dark phase; even in light phase, activity is several-fold increased compared to wild-type controls; this activity is completely abolished in mice raised on doxycycline

immune system
• neuritic pathology is observed around plaques; neuritic pathology is more severe in older mice
• if transgene expression is suppressed with doxycycline treatment, pathology does not progress in severity

homeostasis/metabolism
• doxycycline-mediated suppression of transgenic APPSwInd synthesis leads to parallel reductions of amyloid beta peptide levels
• early onset amyloid formation is observed, with plaques observed as early as 8 weeks of age in mice receiving no doxycycline (DOX) treatment
• plaques are restricted to the forebrain, including the cortex, hippocampus, olfactory bulb, and striatum; by 6 months, amyloid burden covers large cortical and hippocampal areas
• first observed plaques are fibrillar-core deposits; in 6 month old animals, diffuse plaques are apparent and these are abundant at 9 months, while in 9-12 month-old mice, plaques are visible in the thalamus
• no lesions are observed in the cerebellum or brain stem
• animals receiving no treatment display moderate amyloid pathology at 6 months, which progresses to a severe amyloid burden by 9 months
• mice raised for 6 months with no (DOX) treatment, followed by 3 or 6 months of DOX treatment show similar pathology to untreated 6-month old animals, despite relatively long lesion clearance times

Mouse Models of Human Disease
OMIM IDRef(s)
Alzheimer Disease; AD 104300 J:109829


Mouse Genome Informatics
tg3
    Tg(tetO-APPSwInd)107Dbo/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
phenotype not analyzed
• no analysis of single transgenic mice provided