Mutations: MAPT G272V, MAPT P301S
Modification: MAPT: Transgenic
Disease Relevance: Frontotemporal Dementia, Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL6/CBA; backcrossed to C57BL6
Availability: Available through Luc Buée.
THY-Tau22 mice are a model for tau aggregation, a pathological hallmark of Alzheimer's disease as well as numerous tauopathies. With age these mice develop a variety of tau-related neuropathological changes, including tau hyperphosphorylation, neurofibrillary-like tau inclusions, and ghost tangles. Tau pathology is generally mild at three to four months of age, moderate at six to seven months, and extensive at nine months and beyond.
In these mice levels of human tau increase with age. At three months heterozygous mice have four to five-fold higher levels of human tau than endogenous tau in the cortex. At twelve months, levels are approximately five to six-fold higher. Levels are slightly lower in the hippocampus. Only trace levels are detected in the spinal cord (Schindowski et al., 2006).
Behaviorally, these mice display learning and memory diffculties, including deficits in spatial, social, and contextual learning that cannot be attributed to a neuromotor impairment. The mice do not exhibit changes in overall motor activity and do not have gross motor deficits (Schindowski et al., 2006). Non-spatial memory was affected as early as six months, whereas spatial is impaired later, after nine months (Van der Jeugd et al., 2013). Impaired appetitive responding has also been observed (Lo et al., 2013).
The neuropathology and behavioral changes coincide with changes in hippocampal synaptic plasticity. Although LTP appears to be intact, deficits in basal synaptic transmission in the hippocampus have been observed (Schindowski et al., 2006). At nine to ten months heterozygous mice exhibit altered paired pulse facilitation (PPF), a form of presynaptic short-term plasticity. They also have impaired maintenance of long-term depression compared with wild-type littermates (Van der Jeugd et al., 2011).
Transgene containing the cDNA of the 412 amino acid isoform of human 4-repeat tau mutated at sites G272V and P301S under a Thy1.2 promotor.
Available through Luc Buée.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
Heterozygous animals develop tau pathology starting at 3-6 months. Pathology becomes more severe and widespread with age. Neurofibrillary tangle-like inclusions occur (Gallyas and MC1+) along with rare ghost tangles and paired helical filament-like structures (Schindowski et al., 2006).
Loss of cells in the CA1 region of the hippocampus from 12 months as measured by DAPI staining and Nissl/cresyl-violet (Schindowski et al., 2006). Also, a significant reduction in the number of choline acetyltransferase (ChAT)-immunopositive cholinergic neurons in the medial septum has been reported (Belarbi et al., 2011).
Age-dependent increase in the number of GFAP+ astrocytes in the hippocampus (hilus, CA1, CA3), cerebral cortex, corpus callosum (Schindowski et al., 2006).
Changes in LTP/LTD
Altered paired pulse facilitation (PPF), a form of presynaptic short-term plasticity in 9-10 month old heterozygous animals: PPF increased at 10 ms. Also at this age, impaired maintenance of long term depression as compared with wild-type littermates (Van der Jeugd et al., 2011). Deficit in basal synaptic transmission in the hippocampus, but normal LTP (Schindowski et al., 2006).
Non-spatial memory affected as early as 6 months; spatial memory impaired only after 9 months (Van der Jeugd et al., 2013). Impaired appetitive responding (Lo et al., 2013).
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