Species: Mouse
Genes: MAPT
Mutations: MAPT A152T
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Strain Name: C57BL/6-Tg(tetO-MAPT*A152T)L1Lms/J
Genetic Background: C59Bl/6J
Availability: Available as single transgenics: The Jackson Lab Stock# 028979 (cyropreserved) and Stock# 007004 (live)

In humans, the A152T MAPT mutation appears to act as a risk modifier to multiple neurodegenerative diseases, including AD, FTD, and DLB. In contrast, the majority of pathogenic mutations in MAPT are causally linked to FTD. To investigate the consequences of the A152T mutation, this mouse model overexpresses the 1N4R isoform of human tau with the A152T mutation. To separate the effects of the mutation versus tau overexpression, an hTau-WT mouse that overexpresses the 1N4R isoform of wild-type human tau was also created (Maeda et al., 2016).

This model uses the TET-OFF system to regulate tau expression, allowing for temporal control over the transgene. The transcriptional transactivator (tTA) is driven by the CaMKIIα promoter, resulting in preferential forebrain expression of tTA, and thus of transgenic tau under regulation of a minimal promotor with a second-generation tetracycline responsive elements (TRE) promotor, TRE-tight. An advantage of this model is that human tau can be suppressed by adding doxycycline (dox) to the diet.

Compared to non-transgenic controls, hTau-A152T and hTau-WT mice live normal life spans, but with slightly lower body weights.

Consistent with the expected pattern for the CaMKIIα promoter, human tau protein was expressed in forebrain neurons, including in the cortex, hippocampus, amygdala, and striatum. Human tau was not detected in monogenic mice without the CaMKII-tTA transgene, suggesting minimal leakiness of the TRE promotor. Transgenic tau protein levels were about four to five times and three to four times endogenous murine tau and in the cortex and hippocampus, respectively, and were comparable between hTau-WT and hTau-A152T mice. At the mRNA level, hTau-A152T mice expressed 50 percent less tau than hTau-WT mice. The discrepancy between mRNA and protein levels is thought to be caused by reduced turnover of tau with the A152T mutation.

Abnormal accumulations of tau and phosphorylated tau were observed as early as two months in both the hTau-WT and hTau-A152T mice. At eight months, staining with the MC1 antibody, which detects oligomeric and filamentous tau, was less extensive in hTau-A152T than hTau-WT animals. When hTau-A152T mice were treated with dox from six to eight months, abnormal tau staining was completely reversed. GFAP immunostaining demonstrated astrocytosis, but no difference in microglia was observed. Neuronal loss was not observed at six months, but by 20 months neuron loss was observed in the dentate gyrus and CA3 region of the hippocampus, but not in the CA1 region in hTau-A152T mice. Neuronal loss was not observed in hTau-WT animals.

Epileptiform spikes, as recorded by EEG, were increased in hTau-A152T mice and decreased in hTau-WT mice compared to non-transgenic controls. At the mossy fiber synapse, synaptic transmission strength was increased and paired-pulse facilitation was decreased in both hTau-WT and hTau-A152T mice.

At 17 months or older, performance in the Morris water maze was impaired in hTau-A152T mice relative to hTau-WT animals. Nest building was impaired at 10 to 14 months. Social interaction, anxiety, exploratory behavior, and motor functions were unaltered. Monogenic and hTau-WT mice performed similarly to non-transgenic control mice.

Related Strains

hTau^AT

Phenotype Characterization

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References

Mutations Citations

1. MAPT A152T

Research Models Citations

1. hTau-AT (hTau40-AT)

Paper Citations

1. Maeda S, Djukic B, Taneja P, Yu GQ, Lo I, Davis A, Craft R, Guo W, Wang X, Kim D, Ponnusamy R, Gill TM, Masliah E, Mucke L. Expression of A152T human tau causes age-dependent neuronal dysfunction and loss in transgenic mice. EMBO Rep. 2016 Apr;17(4):530-51. Epub 2016 Mar 1 PubMed. Correction.

External Citations

1. The Jackson Lab Stock# 028979
2. Stock# 007004

Further Reading