Phenotypes Associated with This Genotype

Genotype
MGI:3709152

• Allelic Composition: Tg(Camk2a-tTA)1Mmay/0; Tg(tetO-APPSwInd)107Dbo/0
• Genetic Background: involves: C3H/HeJ * C57BL/6 * CBA

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

nervous system

amyloid beta deposits ( J:109829 )

• 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

abnormal dentate gyrus morphology ( J:185792 )

• mice exhibit a progressive neuronal atrophy that is most pronounced in the granule cell layer of hippocampal dentate gyrus

hippocampal neuron degeneration ( J:185792 )

• 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

neurofibrillary tangles ( J:109829 )

• first visible plaques are fibrillary-cored deposits

abnormal astrocyte morphology ( J:109829 )

• 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

abnormal nervous system physiology ( J:109829 )

• 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

CNS inflammation ( J:109829 )

• 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

abnormal locomotor activation ( J:109829 )

• hyperactive behavior is partially reversed in some mice by 1 month of transgene suppression starting at 4-5 months of age

increased locomotor activity ( J:109829 )

• 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

abnormal circadian behavior ( J:109829 )

• all animals raised with doxycycline have altered circadian rhythms with less distinction between day- and nighttime activity levels

immune system

CNS inflammation ( J:109829 )

• 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

amyloid beta deposits ( J:109829 )

• 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		DO ID	OMIM ID(s)	Ref(s)
Alzheimer's disease		DOID:10652		J:109829