immune system phenotype

• CNS inflammation
  • if transgene expression is suppressed with doxycycline treatment, pathology does not progress in severity
  (MGI Ref ID J:109829)
  • neuritic pathology is observed around plaques; neuritic pathology is more severe in older mice
  (MGI Ref ID J:109829)

nervous system phenotype

• abnormal nervous system physiology
  • sensitivity of transgene suppression by doxycycline is intermediate between mice of line 885 and line 102
  (MGI Ref ID J:109829)
  • mice produce transgenic APP protein at 10- to 30-fold over endogenous App levels
  (MGI Ref ID J:109829)

• CNS inflammation
  • neuritic pathology is observed around plaques; neuritic pathology is more severe in older mice
  (MGI Ref ID J:109829)
  • if transgene expression is suppressed with doxycycline treatment, pathology does not progress in severity
  (MGI Ref ID J:109829)

• abnormal astrocyte morphology
  • if transgene expression is suppressed with doxycycline treatment, pathology does not progress in severity
  (MGI Ref ID J:109829)
  • activated astrocytes are found near plaques in all affected mice glial pathology is more severe in older mice
  (MGI Ref ID J:109829)

• amyloid beta deposits
  • animals receiving no treatment display moderate amyloid pathology at 6 months, which progresses to a severe amyloid burden by 9 months
  (MGI Ref ID J:109829)
  • no lesions are observed in the cerebellum or brain stem
  (MGI Ref ID J:109829)
  • doxycycline-mediated suppression of transgenic APPSwInd synthesis leads to parallel reductions of amyloid beta peptide levels
  (MGI Ref ID J:109829)
  • early onset amyloid formation is observed, with plaques observed as early as 8 weeks of age in mice receiving no doxycycline (DOX) treatment
  (MGI Ref ID J:109829)
  • 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
  (MGI Ref ID J:109829)
  • 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
  (MGI Ref ID J:109829)
  • 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
  (MGI Ref ID J:109829)

• hippocampal neuron degeneration
  • mice exhibit a progressive neuronal atrophy that is most pronounced in the granule cell layer of hippocampal dentate gyrus
  (MGI Ref ID J:185792)
  • however, when mice are reared on doxycycline, cell loss is not observed
  (MGI Ref ID J:185792)

• neurofibrillary tangles
  • first visible plaques are fibrillary-cored deposits
  (MGI Ref ID J:109829)

• abnormal dentate gyrus morphology
  • mice exhibit a progressive neuronal atrophy that is most pronounced in the granule cell layer of hippocampal dentate gyrus
  (MGI Ref ID J:185792)

behavior/neurological phenotype

• hyperactivity
  • untreated mice show hyperactivity, often running in circles around the perimeter of cages
  (MGI Ref ID J:109829)
  • similar patterns of activity are observed in Morris water maze, with repetitive swim patterns seen in radial water maze swim test
  (MGI Ref ID J:109829)
  • 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
  (MGI Ref ID J:109829)
  • hyperactive phenotype penetrance is ~100%
  (MGI Ref ID J:109829)

• abnormal circadian behavior
  • all animals raised with doxycycline have altered circadian rhythms with less distinction between day- and nighttime activity levels
  (MGI Ref ID J:109829)

• abnormal locomotor activation
  • hyperactive behavior is partially reversed in some mice by 1 month of transgene suppression starting at 4-5 months of age
  (MGI Ref ID J:109829)

homeostasis/metabolism phenotype

• amyloid beta deposits
  • early onset amyloid formation is observed, with plaques observed as early as 8 weeks of age in mice receiving no doxycycline (DOX) treatment
  (MGI Ref ID J:109829)
  • animals receiving no treatment display moderate amyloid pathology at 6 months, which progresses to a severe amyloid burden by 9 months
  (MGI Ref ID J:109829)
  • no lesions are observed in the cerebellum or brain stem
  (MGI Ref ID J:109829)
  • 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
  (MGI Ref ID J:109829)
  • 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
  (MGI Ref ID J:109829)
  • doxycycline-mediated suppression of transgenic APPSwInd synthesis leads to parallel reductions of amyloid beta peptide levels
  (MGI Ref ID J:109829)
  • 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
  (MGI Ref ID J:109829)

mammalian phenotype

• no phenotypic analysis
  • no analysis of single transgenic mice provided
  (MGI Ref ID J:109829)

behavior/neurological phenotype

• abnormal long term spatial reference memory
  • bi-transgenic mice (on-DOX) perform similar to non-transgenic controls in RAWM
  (MGI Ref ID 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
  (MGI Ref ID J:195259)
  • ent sessions the error rate becomes similar to non-transgenic controls
  (MGI Ref ID 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
  (MGI Ref ID J:195259)

• abnormal spatial working memory
  • 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
  (MGI Ref ID 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)
  (MGI Ref ID J:195259)
  • 12.5 month old bi-transgenic males (on-DOX) exhibit a preference for the new arm
  (MGI Ref ID J:195259)
  • y
  (MGI Ref ID J:195259)

homeostasis/metabolism phenotype

• amyloid beta deposits
  • 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
  (MGI Ref ID J:195259)
  • a low level of mobile, water-extractable Abeta42 is present in bitransgenic males treated with DOX for up to 4 weeks
  (MGI Ref ID J:195259)

mammalian phenotype

• behavior/neurological phenotype
  • Normal - bitransgenic (off-DOX) males perform like wild-type males in Plus water maze apparatus, swimming abilities, and latency to find platform
  (MGI Ref ID J:195259)

nervous system phenotype

• amyloid beta deposits
  • a low level of mobile, water-extractable Abeta42 is present in bitransgenic males treated with DOX for up to 4 weeks
  (MGI Ref ID J:195259)
  • 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
  (MGI Ref ID J:195259)