Phenotypes Associated with This Genotype

Genotype
MGI:5554193

• Allelic Composition: Tg(Camk2a-tTA)1Mmay/0; Tg(tetO-MAPT*K280,-luc)#Eman/0
• Genetic Background: involves: C57BL/6

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

nervous system

neurofibrillary tangles ( J:131379 , J:169532 )

• tau tangles are seen as early as 2-3 months after doxycycline removal (at 6 weeks after birth to induce gene expression) in the entorhinal cortex and amygdala (J:131379)

• by 15 months after doxycycline removal, neurofibrillary tangles are seen in the neocortex (J:131379)

• neurofibrillary tangles persist in mice that are doxycycline treated for 4 months after 10 months of transgene expression (J:131379)

tau protein deposits ( J:131379 , J:169532 )

• tau aggregates are seen in the cortex as early as 2-3 months after doxycycline removal (at 6 weeks after birth to induce gene expression) (J:131379)

• tau aggregates include both endogenous and the exogenous tau protein (J:131379)

• when expression is switched off by addition of doxycycline, soluble and aggregated exogenous tau disappears within 1.5 months, however tangles of mouse tau remain (J:131379)

• tau aggregates are seen at 10 months after doxycycline removal to switch on expression (J:131379)

• moderate reduction in tau aggregates is seen in mice that express the transgene for 10 months and then are switched off with doxycycline treatment for 4 months (J:131379)

• exogenous tau disappears from tau aggregates in mice that express the transgene for 10 months and then are switched off with doxycycline treatment for 4 months (J:131379)

• missorting of tau into the somatodendritic compartment of cortical and hippocampal neurons is seen after doxycycline removal (J:131379)

astrocytosis ( J:131379 , J:169532 )

• astrogliosis is seen in the hilus region 21 months after doxycycline removal (J:131379)

• activated astrocytes are detected inside the dentate gyrus after doxycycline removal, indicating inflammatory processes (J:169532)

abnormal neurite morphology ( J:131379 )

• by 15 months after doxycycline removal, dystrophic neurites are seen

abnormal synapse morphology ( J:131379 , J:169532 )

• loss of spine synapses and a decrease in presynaptic proteins in the hippocampus is seen after 9.5 months without doxycycline (J:131379)

• synapses decrease by about 30% after 10 months of expression (doxycycline removal) but only by about 15% when expression is then switched off with doxycycline treatment for 4 months, indicating some recovery of synapses (J:131379)

neuron degeneration ( J:131379 , J:169532 )

• some neurons that lack neurofibrillary tangles exhibit incipient degeneration as early as 2-3 months after doxycycline removal (J:131379)

• neuronal loss is seen in the granule cells of the dentate gyrus starting at 5 months after doxycycline removal and is increased at 24 months of gene expression such that shrinkage of the molecular layer is observed (J:131379)

• when expression is switched off again by addition of doxycycline for 1.5 months, the hippocampal pyramidal areas that retain neurofibrillary tangles display neuronal loss (J:131379)

• neuronal loss is seen at 10 months after doxycycline removal in different regions of the hippocampus and cortex (J:169532)

• neuronal loss is seen in the CA1 and dentate gyrus region of the hippocampus in mice that express the transgene for 10 months and then are switched off with doxycycline treatment for 4 months (J:169532)

impaired synaptic plasticity ( J:169532 )

• mice at 10 months after doxycycline removal show reduced short term plasticity at the mossy fiber-CA3 synapse

• impairment of synaptic facilitation in mice at 10 months after doxycycline removal; this impairment is reversible after expression of the transgene is switched off with doxycycline treatment for 4 months

• mice at 10 months after doxycycline removal show reduced frequency facilitation induced by continuous stimulation at 1 Hz for 1 min; switching off transgene expression with doxycycline for 4 months partially restores the initial rising phase of frequency facilitation

reduced long-term potentiation ( J:169532 )

• LTP is impaired in CA3 and CA1 areas of the hippocampus in mice at 10 months after doxycycline removal; LTP is recovered after expression of the transgene is switched off with doxycycline treatment for 4 months

decreased post-tetanic potentiation ( J:169532 )

• posttetanic potentiation (PTP) is reduced in CA3 areas of the hippocampus in mice at 10 months after doxycycline removal; PTP is recovered after expression of the transgene is switched off with doxycycline treatment for 4 months

behavior/neurological

impaired passive avoidance behavior ( J:169532 )

• mice at 10 months after doxycycline removal exhibit impaired memory in the passive avoidance test, reentering the dark compartment where mild footshock was introduced faster than controls which avoid the compartment

impaired spatial learning ( J:169532 )

• in the Morris water maze task, mice 10 months after doxycycline removal show a slower rate of learning to find the submerged escape platform, especially at days 2 and 3 of training

• however, mice show normal behavior in the probe trial after the acquisition phase

• in reversal learning during which the platform is transferred to another quadrant, mice at 14 months after doxycycline removal are slower to reach the platform on days 2 and 3 compared to wild-type mice or mutant mice in which expression was turned off with doxycycline treatment for 4 months, and they spend more time searching the former target quadrant than the quadrant where the platform is now located

impaired coordination ( J:169532 )

• lower rotarod performance at 10 months after doxycycline removal to induce expression, showing a lower performance on the first two trial but normal performance in the last trial

• however, grip strength and performance in spontaneous home cage activity is normal at 10 months after doxycycline removal

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Alzheimer's disease		DOID:10652		J:131379 , J:169532