Species: Mouse
Genes: MAPT
Mutations: MAPT A152T
Modification: MAPT: Knock-In
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Strain Name: N/A
Genetic Background: C57BL/6
Availability: Available through Eva Mandelkow

In humans, the A152T MAPT mutation appears to act as a risk modifier to multiple neurodegenerative diseases including AD, FTD, and DLB. In contrast, the majority of pathogenic mutations in MAPT are causally linked to FTD. To investigate the consequences of the A152T mutation, this mouse model overexpresses the 2N4R isoform of human tau with the A152T mutation. Two papers refer to this mouse variously as the hTau^AT or hTau40^AT mouse line (Decker et al., 2016; Sydow et al., 2016).

Consistent with the expected pattern for the Thy1.2 promoter, human tau protein was expressed in neurons throughout the brain and spinal cord. Transgenic tau protein levels were about 2x, 1x, 3x, and 1.5x endogenous murine tau and in the cortex, hippocampus, spinal cord, and cerebellum, respectively. At the mRNA level, hTau^AT mice expressed equivalent levels of transgenic and murine tau in the hippocampus.

As early as two months, transgenic tau was mislocalized to the somato-dendritic compartment. Dense neurofibrillary tangles were observed in the hippocampus, cortex, cerebellum, and spinal cord starting at three months and increasing with age. Tau was also found to be hyperphosphorylated and in pathological conformations at three months. Analysis of protein levels from cortical extracts suggested alterations in the autophagosome and proteasome pathways.

Immunostaining demonstrated astrocytosis, microgliosis, and neuroinflammation at 10 months of age. Neuronal loss was detected in the hippocampus and cortex mice at 12 months of age.

There was no difference between 10-month-old hTau^AT mice and controls in the number of spines on the apical dendrites of CA1 pyramidal neurons. At 12 months, though, apical dendrites in CA3 had increased spine numbers by Golgi staining, which was associated with increased neuronal activity. At the protein level there was a decrease in the amount of synaptophysin, but not PSD95, and ultrastructural analysis found swollen synaptic vesicles but postsynaptic densities appeared normal. At 20 months, there was a reduction in spine number in CA1 and CA3 apical dendrites, suggesting age-dependent synapse loss. Mossy fiber synapses had an increase in basal synaptic transmission, but no changes were detected in LTP or paired-pulse facilitation.

Slice cultures from hTau^AT mice had increased extracellular glutamate, which increased intracellular Ca⁺⁺ concentrations through NMDA receptors and L-type Ca⁺⁺ channels. Increased epileptiform activity in slice cultures was prevented by upregulating glutamate transporters to clear excess extracellular glutamate.

In the Morris water maze, learning and memory were impaired at 16 months, but not at 10 months. No motor deficits were detected in swim speed, gait analysis, or the Rotarod test.

Related Strains

hTau-A152T

Phenotype Characterization

COMMENTS / QUESTIONS

No Available Comments

Make a comment or submit a question

To make a comment you must login or register.

References

Mutations Citations

1. MAPT A152T

Research Models Citations

1. hTau-A152T

Paper Citations

1. Decker JM, Krüger L, Sydow A, Dennissen FJ, Siskova Z, Mandelkow E, Mandelkow EM. The Tau/A152T mutation, a risk factor for frontotemporal-spectrum disorders, leads to NR2B receptor-mediated excitotoxicity. EMBO Rep. 2016 Apr;17(4):552-69. Epub 2016 Mar 1 PubMed.
2. Sydow A, Hochgräfe K, Könen S, Cadinu D, Matenia D, Petrova O, Joseph M, Dennissen FJ, Mandelkow EM. Age-dependent neuroinflammation and cognitive decline in a novel Ala152Thr-Tau transgenic mouse model of PSP and AD. Acta Neuropathol Commun. 2016 Feb 25;4:17. PubMed.

Other Citations

1. Eva Mandelkow

Further Reading