Mutations: MAPT L266V, MAPT G272V
Modification: MAPT: Transgenic
Disease Relevance: Frontotemporal Dementia, Pick's disease, Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL/6 x DBA/2F1, crossed with DBA
This transgenic mouse is rare among tauopathy models because it was engineered to overexpress mutant tau with three microtubule binding repeat domains (3R tau), rather than four domains (4R tau). The transgene includes two mutations associated with familial Pick’s disease, L266V and G272V, and like human mutation carriers, the mice develop neuronal tau inclusions described as Pick bodies. The mice also develop age-related neurodegeneration in the hippocampus and cortex as well as behavioral deficits indicative of cognitive and motor impairment.
Two lines of mThy-1 3R tau mice were generated in parallel: line 2 (a low-expressing line) and line 13 (a high-expressing line) (Rockenstein et al., 2015). Line 2 expresses 3R tau at levels just slightly higher than endogenous 3R tau, whereas line 13 produces about eight times more. Line 13 had a more severe phenotype and heterozygous mice from line 13 are described on this page, unless otherwise noted.
In line 13 mice, mutant human tau protein accumulated with age, with high expression in pyramidal neurons in layers II-III and V of the neocortex, as well as in pyramidal and granular cells of the hippocampus. Phosphorylated tau forms were also elevated in these neurons. By eight and 10 months of age, line 13 mice displayed intraneuronal tau aggregates in the frontal cortex. These were positive for Bielschowsky silver stain but negative for Gallyas silver stain and Thioflavin-S. Fibrillar and globular tau deposits were seen, the latter reminiscent of Pick bodies. These were positive for a variety of antibodies against 3R tau, phospho-tau, and ubiquitin.
Neurodegeneration was seen in 8- to 10-month-old animals, as evidenced by reduced neuronal density the hippocampus as well as decreased neocortical volume. Dendritic density was also lower. Three-R tau was also seen in GFAP-positive astrocytes. It is unclear if this is due to ectopic expression of the Thy-1 driven transgene or uptake of human 3R tau into glial cells. Neurodegeneration was accompanied by astrocytosis in the hippocampus and cortex. Other neuropathological phenotypes included enlarged and disorganized mitochondria, axonal dystrophy, and dendritic abnormalities, including elevated levels of 3R tau in dendrites.
Behaviorally, line 13 mice displayed memory impairment as indicated by a failure to habituate to a novel environment (i.e., context-dependent learning). This deficit was not apparent at 3-4 months of age, but became evident by 6-8 months and 12-14 months. Further evidence of memory impairment was seen in the Morris water maze, with 8- to 10-month-old animals taking longer to find the hidden platform than wild-type and line 2 mice.
Line 13 mice displayed higher levels of total activity by 3 to 4 months of age, which continued as they aged. They also displayed elevated levels of thigmotaxis, a tendency to stay close to walls, suggestive of increased anxiety relative to wild-type mice.
On the round beam, a test of gait and balance, line 13 mice made more errors than line 2 or wild-type mice. This deficit emerged by 6-8 months of age and was more severe in 12- to 14-month-old animals.
These transgenic mice overexpress human 3R tau bearing the L266V and G272V mutations under the neuronal mThy-1 promoter.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Synaptic Loss
- Changes in LTP/LTD
Pick-body like inclusions of aggregated tau appeared in the hippocampus and cortex by 8-10 months. Inclusions were positive for Bielchowsky silver stain but negative for Gallyas-silver stain and Thioflavin-S.
Neuronal loss occurred by 8-10 months as evidenced by decreased NeuN staining in the dentate gyrus and CA3 regions of the hippocampus. Neocortical volume also decreased.
Astrogliosis was seen by 8-10 months in the neocortex and hippocampus. Some GFAP+ astrocytes also contained 3R tau.
Synapto-dendritic damage manifested as reduced dendritic density, reduced MAP2 immunoreactivity, and accumulation of 3R tau in dendrites.
Changes in LTP/LTD
By 6-8 months memory impairment was evident as a failure to habituate to a novel environment. This deficit was not present at 3-4 months. At 8-10 months, transgenics also took longer than wild-type mice to find the hidden platform in the Morris water maze.
- Rockenstein E, Overk CR, Ubhi K, Mante M, Patrick C, Adame A, Bisquert A, Trejo-Morales M, Spencer B, Masliah E. A novel triple repeat mutant tau transgenic model that mimics aspects of pick's disease and fronto-temporal tauopathies. PLoS One. 2015;10(3):e0121570. Epub 2015 Mar 24 PubMed.
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