Mutations: MAPT P301L
Modification: MAPT: Transgenic
Disease Relevance: Frontotemporal Dementia, Alzheimer's Disease
Strain Name: N/A
Genetic Background: 4510 mice are on an FVB background. Neuropsin-tTA mice are on a C57BL/6 background.
This transgenic model uses the Tet-OFF system to express mutant human tau preferentially in a subset of entorhinal neurons (de Calignon et al., 2012). The bigenic mice develop age-related tau pathology, first in the entorhinal cortex (EC) and later spreading to neighboring brain regions, notably areas that are functionally connected to the EC. The pattern of tau propagation in these mice supports the hypothesis that toxic tau can be transmitted through neural circuits in a manner that may shed light on the progression of pathology in the human brain.
rTgTauEC bigenic mice are made by crossing an activator line, neuropsin-tTA, with a responder line, Tg(tauP301L)4510. The neuropsin promoter drives the tetracycline transactivator (tTA) transgene preferentially in a subset of neurons in the entorhinal cortex (Yasuda and Mayford, 2006). When crossed with Tg(tauP301L)4510, mutatnt tau expression was indeed concentrated in the EC, with intense mRNA and protein expression by 3 months of age in a subset of EC neurons, primarily layer II. Some expression was also observed in the pre- and parasubiculum with sporadic expression in hippocampal neurons of the dentate gyrus, CA1, and CA3 regions. Of note, the degree of Nop-tTA “leakiness” may depend on factors related to genetic background and should be carefully characterized in each experimental cohort (see Yetman et al., 2015 and the Rodent Brain Workbench tTA atlas).
Neuropathologically, these mice develop a stereotyped progression of tau pathology as they age. Tau pathology starts around 3 months of age with misfolded tau in the EC, as indicated by Alz50 staining. The misfolded tau progresses into Gallyas silver-positive paired helical filaments by 18 months of age, followed by mature thioflavin–S positive tangles, by 24 months of age (de Calignon et al., 2012).
Neurodegeneration occurs in older rTgTauEC mice. Significant neuronal loss was detected at 24 months of age in areas with transgene expression, namely, layer II of the EC and parasubiculum, compared with neuronal numbers in littermates expressing tTA alone. Neuronal loss was ultimately quite severe, about 42 percent loss in the EC by 24 months of age, but changes were not detectable at 21 months of age, suggesting neuronal degeneration is a relatively late phenotype. Axonal degeneration, synapse loss, and gliosis were also observed at advanced age (de Calignon et al., 2012).
Behavioral deficits in rTgTauEC mice are subtle. For example, a minor decrease in the total distance travelled was measured in the open-field test. However, this test did not show elevated levels of anxiety or changes in exploration. Performance on the rotarod was normal. At 16 months of age, behavior in the radial-arm maze was comparable to control mice suggesting spatial memory was intact. Subtle differences in contextual fear conditioning were observed at 16 months, but not at nine months of age (Polydoro et al., 2014).
In addition, at 16 months of age, subtle differences in electrophysiological properties have been observed in the perforant pathway, through which the EC innervates the dentate gyrus. Specifically, a decrease in LTP and an increase in the probability of neurotransmitter release were observed. These changes are detectable relatively early, prior to tangle formation or neurodegeneration (Polydoro et al., 2014).
Data described in this entry were reported in heterozygous mice.
The integration site of the MAPT transgene in Tg(TauP301L)4510 is within the Fgf14 (fibroblast growth factor 14) gene on chromosome 14, resulting in a 244 Kb deletion that includes exon 1 (Goodwin et al., 2017). To what extent, if any, disruption of this mouse gene contributes to the development of the rTgTauEC phenotype awaits further study.
Nop-tTA-tau (NT) -An independently generated regulatable transgenic model that also results from crossing Nop-tTA activator mice with Tg(tauP301L)4510 responder mice (Liu et al., 2012).
EC-hTau—An independently generated regulatable transgenic model that also results from crossing of Nop-tTA activator mice with Tg(tauP301L)4510 responder mice (Harris et al., 2012).
rTg4510 - Bitransgenic line that results from crossing CaMKIIα-tTA activator mice with Tg(tauP301L)4510 responder mice. Expression of mutatnt tau is restricted to forebrain neurons.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
By 18 months of age, Gallyas silver-positive staining is observed, indicative of paired helical filaments. This is followed by thioflavin-S staining at 24 months. Tau pathology develops first in neurons of the medial EC expressing human tau, followed by neurons in the dentate gyrus, CA1 and CA2/3(de Calignon et al., 2012).
Neuronal loss is detectable by 24 months of age in areas with transgene expression (e.g. layer II of the EC and parasubiculum), compared with age-matched mice expressing only tTA. Significant neuronal loss was not observed at 21 months (de Calignon et al., 2012).
Microglial activation and astrogliosis by 24 months of age, in conjunction with axonal degeneration and neuronal loss (de Calignon et al., 2012).
By 24 months of age pre- and post-synaptic densities were reduced in the middle third of the molecular layer of the dentate gyrus as measured by synapsin-1 and PSD-95 staining (de Calignon et al., 2012).
Changes in LTP/LTD
At 16 months of age, subtle differences in electrophysiological properties have been observed in the perforant pathway, including a decrease in LTP and an increase in the probability of neurotransmitter release (Polydoro et al., 2014).
Very mild and specific deficits in contextual fear conditioning at 16 months of age, but no deficits in the radial arm maze (Polydoro et al., 2014).
Last Updated: 13 Apr 2018
Research Models Citations
- de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, Spires-Jones TL, Hyman BT. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron. 2012 Feb 23;73(4):685-97. PubMed.
- Yasuda M, Mayford MR. CaMKII activation in the entorhinal cortex disrupts previously encoded spatial memory. Neuron. 2006 Apr 20;50(2):309-18. PubMed.
- Yetman MJ, Lillehaug S, Bjaalie JG, Leergaard TB, Jankowsky JL. Transgene expression in the Nop-tTA driver line is not inherently restricted to the entorhinal cortex. Brain Struct Funct. 2015 Apr 14; PubMed.
- Polydoro M, Dzhala VI, Pooler AM, Nicholls SB, McKinney AP, Sanchez L, Pitstick R, Carlson GA, Staley KJ, Spires-Jones TL, Hyman BT. Soluble pathological tau in the entorhinal cortex leads to presynaptic deficits in an early Alzheimer's disease model. Acta Neuropathol. 2014 Feb;127(2):257-70. Epub 2013 Nov 24 PubMed.
- Goodwin LO, Splinter E, Davis TL, Urban R, He H, Braun RE, Chesler EJ, Kumar V, van Min M, Ndukum J, Philip VM, Reinholdt LG, Svenson K, White JK, Sasner M, Lutz C, Murray SA. Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis. bioRxiv preprint first posted online Dec. 18, 2017
- Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C, Duff K. Trans-synaptic spread of tau pathology in vivo. PLoS One. 2012;7(2):e31302. PubMed.
- Harris JA, Koyama A, Maeda S, Ho K, Devidze N, Dubal DB, Yu GQ, Masliah E, Mucke L. Human P301L-mutant tau expression in mouse entorhinal-hippocampal network causes tau aggregation and presynaptic pathology but no cognitive deficits. PLoS One. 2012;7(9):e45881. PubMed.
- Pooler AM, Polydoro M, Wegmann SK, Pitstick R, Kay KR, Sanchez L, Carlson GA, Gomez-Isla T, Albers MW, Spires-Jones TL, Hyman BT. Tau - amyloid interactions in the rTgTauEC model of early Alzheimer's disease suggest amyloid induced disruption of axonal projections and exacerbated axonal pathology. J Comp Neurol. 2013 Jul 10; PubMed.
- Spires-Jones TL, Hyman BT. The intersection of amyloid beta and tau at synapses in Alzheimer's disease. Neuron. 2014 May 21;82(4):756-71. PubMed.