Mutations: MAPT P301L
Modification: MAPT: Transgenic
Disease Relevance: Frontotemporal Dementia, Progressive Supranuclear Palsy, Alzheimer's Disease
Strain Name: Tg(Prnp-MAPT*P301L)JNPL3Hlmc
Genetic Background: C57BL/6, DBA/2, SW Mixed Background
Availability: Taconic: Stock#2508 (homozygote); #1638 (heterozygote and wild-type) has been discontinued.
These mice were developed in the lab of Mike Hutton at the Mayo Clinic and have been maintained by Taconic since 2000. As originally described, the hemizygous animals express human tau at levels comparable to endogenous murine tau, whereas homozygotes express human tau at approximately twice endogenous levels. Transgene expression was strongest in the cerebellum and hippocampus, followed by the thalamus, hypothalamus, spindal cord, brainstem and cortex. Behaviorally, they develop motor impairment, with 90 percent of animals exhibiting motor and behavioral problems by ten months. They also have limb weakness, a hunched posture, and decreases in grooming and vocalization. Eye irritation is also common, possibily due to carrying the Pde6brd1 retinal degeneration allele (Lewis et al., 2000).
These mice carry a transgene encoding human tau with four microtubule-binding repeat domains and no N-terminal inserts (4R/0N). The transgene contains the P301L mutation and expression is driven by the mouse prion promoter.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Cognitive Impairment
Neurofibrillary tangles develop in an age and gene-dose dependent manner; as early as 4.5 months in homozygotes and 6.5 months in heterozygotes. Tangles and Pick-body-like neuronal inclusions in the amygdala, septal nuclei, preoptic nuclei, hypothalamus, midbrain, pons, medulla, deep cerebellar nuclei and spinal cord (Lewis et al., 2000).
Neuronal loss, especially in the spinal cord, most prominent in the anterior horn (Lewis et al., 2000).
Astrogliosis (as measured by GFAP reactivity) in brainstem, diencephalon, and basal telencephalon by 10 months (Lewis et al., 2000).
- Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, Gwinn-Hardy K, Paul Murphy M, Baker M, Yu X, Duff K, Hardy J, Corral A, Lin WL, Yen SH, Dickson DW, Davies P, Hutton M. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet. 2000 Aug;25(4):402-5. PubMed.