Mouse Genome Informatics
cx
    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