Species: Mouse
Genes: MAPT
Mutations: MAPT A152T
Modification: MAPT: Virus
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Strain Name: N/A
Genetic Background: C57BL/6
Availability: Unknown.

Summary

The A152T variant of MAPT acts as a risk modifier that increases susceptibility to several neurodegenerative conditions, including Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies. Tau^152T-AAV mice were created to explore the mechanisms through which this mutation might affect disease risk. To generate this model, an adeno-associated viral (AAV) vector encoding human tau with the A152T mutation was injected into the ventricles of neonatal mice. Tau^A152T-AAV mice were characterized biochemically, neuropathologically, and behaviorally at 3 months of age and compared with control mice injected with AAV carrying a gene encoding green fluorescent protein (GFP-AAV) and with Tau^P301L-AAV mice, which express human tau with the P301L mutation linked to frontotemporal dementia. At 3 months of age, Tau^A152T-AAV mice exhibited behavioral abnormalities, astrogliosis, cortical neuron loss, and the accumulation of hyperphosphorylated tau. However, hyperphosphorylated tau from the brains of Tau^A152T-AAV mice was soluble in buffers containing the detergent sarkosyl, in contrast with hyperphosphorylated tau from the brains of Tau^P301L-AAV mice, which formed sarkosyl-insoluble aggregates.

Human tau was expressed throughout the brains and in the spinal cords of Tau^A152T-AAV and Tau^P301L-AAV mice. While the two models expressed similar levels of MAPT mRNA in the brain, human tau protein levels were lower in Tau^A152T-AAV mice.

Biochemical analyses revealed striking differences between tau extracted from the brains of Tau^A152T-AAV and Tau^P301L-AAV mice. When tau species were separated based on their solubility in different buffers, tau from Tau^P301L-AAV mice was found to distribute into three fractions: tau that was soluble in buffered saline, tau that was soluble in buffered saline containing the detergent sarkosyl, and tau that was insoluble in either of these buffers; hyperphosphorylated tau accumulated in the insoluble fraction, indicating that this tau is likely found in aggregates (Greenberg and Davies, 1990). Almost all tau from the brains of Tau^A152T-AAV mice was soluble in buffered saline (with or without sarkosyl), even hyperphosphorylated tau. Among the phospho-tau species found in the soluble fractions from Tau^A152T-AAV brains, but in the insoluble fraction from Tau^P301L-AAV brains, was pT153—tau phosphorylated at the threonine adjacent to the mutated residue at amino acid 152. The solubility profile of pT153 from Tau^A152T-AAV mice appears to mimic that that in humans: The presence of soluble pT153 was found to differentiate A152T carriers from noncarriers in a small autopsy sample that included specimens from subjects with Alzheimer’s disease, progressive supranuclear palsy, Lewy body dementia, and corticobasal degeneration.

Neuropathology

Immunostaining with monoclonal antibody CP13, which recognizes tau phosphorylated at serine-202, resulted in diffuse labeling throughout the brains of Tau^A152T-AAV mice. There was minimal labeling with monoclonal antibody MC1, a conformation-selective antibody that is believed to recognize pre-tangles. By contrast, pronounced MC1 immunoreactivity was seen in the brains of Tau^P301L-AAV mice, and CP13 immunoreactivity appeared as strong punctate labeling of cell bodies.

Astrogliosis was present in the cortices of both Tau^A152T-AAV and Tau^P301L-AAV mice. Microgliosis was not observed in Tau^A152T-AAV, although it was seen in Tau^P301L-AAV brains.

Neuron loss, evaluated as a reduction in the number of NeuN-immunoreactive nuclei, was observed in the cortices of Tau^A152T-AAV mice. No neuron loss was seen in Tau^P301L-AAV cortex.

Behavior

Compared with GFP-AAV controls, Tau^A152T-AAV mice showed deficits in contextual and cued fear conditioning, increased hyperactivity and decreased rearing in the open-field test, and spent more time in the open arms of the elevated plus maze. Tau^A152T-AAV mice also exhibited motor impairment on the Rotarod. 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.

Modification Details

An adeno-associated viral (AAV1) vector encoding TauA152T under the control of the cytomegalovirus enhancer/chicken β-actin promoter was injected bilaterally into the lateral ventricles of neonatal C57BL/6 mice.

Phenotype Characterization

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References

Research Models Citations

1. TauP301L-AAV

Paper Citations

1. Greenberg SG, Davies P. A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5827-31. PubMed.

Further Reading

No Available Further Reading