Mutations: MAPT IVS10+16 C>T
Modification: MAPT: Transgenic
Disease Relevance: Frontotemporal Dementia, Alzheimer's Disease, Other Tauopathy
Strain Name: N/A
Genetic Background: B6C3F1 embryos, backcrossed to C57BL/6
Availability: Available through Hiroshi Mori and Takami Tomiyama
This transgenic mouse expresses relatively low levels of a human tau transgene carrying an intronic mutation associated with tau-related neurodegenerative disease (FTDP-17) in several families. The model recapitulates disease-related phenotypes, including hyperphosphorylated tau tangles and neuronal loss in the entorhinal cortex and hippocampus. In addition to modeling aspects of human disease, this mouse demonstrated that a non-coding intronic mutation was sufficient to induce neuropathological changes in vivo by altering the relative production of wild-type 3-repeat (3R) and 4-repeat (4R) tau isoforms in the brain (Umeda et al., 2013; Umeda et al., 2015).
Two lines of mice carrying the MAPT intronic 10 + 16 C>T mutation were reported simultaneously, line 609 (Tau609) and line 784 (Tau784). The phenotypes in these two lines are very similar. Tau609 and Tau784 express human tau at levels of about 66 percent and 88 percent, respectively, of endogenous mouse tau levels. The findings on this page refer to heterozygous animals in the Tau609 line.
These mice develop several neuropathological and cognitive features of human tauopathies, including hyperphosphorylated tau, tau tangles, neuronal loss, and memory deficits. These phenotypes are age-associated, with the first signs of pathology developing around six months of age with the appearance of hyperphosphorylated tau in hippocampal mossy fibers and a reduction in synaptic density in select regions of the hippocampus. Intraneuronal tau tangles are evident by 15 months of age as demonstrated by Gallyas silver-positive staining. Neuronal loss is also evident by 15 months of age, as demonstrated by reduced numbers of NeuN-positive cells in layer II of the entorhinal cortex compared with non-Tg littermates.
Behaviorally, these mice demonstrate spatial memory deficits starting around six months of age. Deficits affect both memory acquisition and memory retention as measured by tasks in the Morris water maze. Differences were not observed in four-month-old animals.
A key feature of these mice is that they process the human tau transgene in a physiological manner, using endogenous splicing machinery to create transcripts that include exon 10 (exon10+) as well as those that exclude it (exon 10-). Respectively, these transcripts generate isoforms containing four microtubule binding repeat domains (4R tau) or three microtubule binding repeat domains (3R tau). By four months of age, predominantly 4R transcripts are expressed, resulting in a preponderance of 4R tau isoforms. This imbalance in the ratio of 3R to 4R tau isoforms confirms in vitro work implicating this intronic location in the regulation of exon 10 splicing.
This model expresses a tau minigene driven by the mouse CAMKIIα promoter. The minigene encodes human tau 441, including partial intronic sequences flanking exon 10 of MAPT. The intronic mutation, IVS10 +16 C>T, was introduced by site-directed mutagenesis.
Tau264: This mouse strain expresses wild-type human tau and has been used as a control.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
Gallyas silver-positive intracellular inclusions of hyperphosphorylated tau aggregates in the entorhinal cortex at 15 months, and in the hippocampus and cerebral cortex at 24 months, but not at 18 months.
Significant loss of NeuN-positive neurons in layer II of the entorhinal cortex at 15 months, and in the hippocampal CA1 region at 24 months, compared with non-Tg controls. No difference in the hippocampus at 18 months.
At 12 months of age, Iba1-positive cells are observed. GFAP is observed at 24 months of age.
Reduced synaptic density at 6 months of age in select hippocampal areas compared to non-Tg mice and those expressing wild-type human tau. Densities in other areas were comparable until later ages (i.e., 24 months).
Changes in LTP/LTD
Some changes in basal synaptic transmission and significant impairment of LTP evident by 6 months of age in some regions of the hippocampus.
Deficits in spatial reference memory by 6 months of age as measured by the Morris water maze. No difference from non-Tg littermates at 4 months of age.
Research Models Citations
- Umeda T, Yamashita T, Kimura T, Ohnishi K, Takuma H, Ozeki T, Takashima A, Tomiyama T, Mori H. Neurodegenerative disorder FTDP-17-related tau intron 10 +16C → T mutation increases tau exon 10 splicing and causes tauopathy in transgenic mice. Am J Pathol. 2013 Jul;183(1):211-25. PubMed.
No Available Further Reading