Species: Mouse
Genes: MAPT
Mutations: MAPT P301L
Modification: MAPT: Virus
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Strain Name: N/A
Genetic Background: C57BL/6
Availability: Unknown.

Summary

To create this model, an adeno-associated viral (AAV) vector encoding human tau with the P301L mutation was injected into the ventricles of neonatal mice. At 6 months of age, Tau^P301L-AAV mice exhibit neurofibrillary tangles, gliosis, and behavioral deficits, but no cortical neuron loss.

Unless specified otherwise, the description on this page refers to 6-month-old mice.

Human tau was expressed throughout the brain, most prominently in the cortex, hippocampus, thalamus, and midbrain. The level of human tau, measured in the forebrains of 6-month animals, was three times that of endogenous mouse tau.

Neuropathology

Tau^P301L-AAV mice developed neurofibrillary pathology. Neurons in the hippocampus and cortex were stained using monoclonal antibodies PHF1 (pS396/404), CP13 (pS202), and MC1 (conformation-specific epitope). Mature neurofibrillary tangles were demonstrated by Gallyas silver staining, Thioflavin S staining, and by the staining of proteinase K-resistant inclusions with the tau-conformation-dependent antibody Ab39. Pre-tangles, mature neurofibrillary tangles, neuropil threads, and dystrophic neurites were observed ultrastructurally.

Ubiquitinated inclusions were seen in neurons of Tau^P301L-AAV mice but not control GFP-AAV mice.

Microgliosis and astrogliosis were seen in the hippocampus and cortex, accompanied by increased expression of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α. Gliosis was also observed in a separate cohort of mice studied at 3 months of age (Carlomagno et al., 2019).

Although synaptic structure and function were not assessed directly, the accumulation of a 50-kDa fragment of PSD95, believed to be generated by calpain cleavage, suggests the possibility of synaptic abnormalities.

Cortical neuron numbers were similar in Tau^P301L-AAV mice and control GFP-AAV mice.

Behavior

Compared with GFP-AAV mice, Tau^P301L-AAV mice exhibited hyperactivity in the open field, decreased time spent in the center of open field (perhaps reflecting increased anxiety), more time spent in the open arms of the elevated plus maze (perhaps indicative of aberrant exploratory behavior and disinhibition), and deficits in cued and contextual fear conditioning. In a separate cohort of mice studied at 3 months of age, Tau^P301L-AAV performed similarly to GFP-AAV mice in the fear-conditioning test, open-field test, and Rotarod, but spent more time in the open arms of the elevated plus maze (Carlomagno et al., 2019).

Modification Details

An adeno-associated viral (AAV1) vector encoding TauP301L under the control of the cytomegalovirus enhancer/chicken β-actin promoter was injected bilaterally into the lateral ventricles of neonatal C57BL/6 mice.

Control mice were injected with AAV1 vectors expressing green fluorescent protein (GFP).

Phenotype Characterization

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References

Paper Citations

1. Carlomagno Y, Chung DC, Yue M, Kurti A, Avendano NM, Castanedes-Casey M, Hinkle KM, Jansen-West K, Daughrity LM, Tong J, Phillips V, Rademakers R, DeTure M, Fryer JD, Dickson DW, Petrucelli L, Cook C. Enhanced phosphorylation of T153 in soluble tau is a defining biochemical feature of the A152T tau risk variant. Acta Neuropathol Commun. 2019 Jan 23;7(1):10. PubMed.

Further Reading

No Available Further Reading