General Information

Development

Using pro-nuclear stage embryos of mice with the knock-in PSEN1 (PS1M146V) mutation, microinjection was used to introduce human APP Swedish and MAPT P301L mutant genes. These two genes are integrated at a single locus under the control of the mouse Thy1.2 promoter.

The 3xTg-AD mice are a widely used model for familial Alzheimer's disease, which includes three gene mutations (APP Swedish, MAPT P301L, and PSEN1 M146V). These mice are viable, fertile, and do not exhibit physiological or behavioral abnormalities in the early stages. The overexpressed transgenic protein products are limited to the central nervous system, including the hippocampus and the cerebral cortex, and typically exhibit characteristics of neurofibrillary tangles and amyloid peptide deposition degeneration after the age of 6 months. The deposition of β-amyloid (Amyloid-beta, Aβ) is gradual, with the earliest detectable intracellular immune response in certain areas of the mouse brain at around 3 to 4 months of age. At 6 months of age, extracellular Aβ deposits appear in the frontal cortex, and by 12 months of age, they are more widely distributed. Changes in tau protein occur subsequently, and by 12 to 15 months of age, highly phosphorylated tau protein aggregates can be detected in the hippocampal region.

Phenotype

1. Neuropathology: These mouse models exhibit age-related, progressive neuropathology, including plaques and tangles. Extraacellular β-amyloid (Amyloid-beta, Aβ) is observed in the frontal cortex at 6 months of age and becomes more widespread by 12 months of age. Although tau pathology is not observed within 6 months, it becomes quite evident by 12 months of age. Synaptic dysfunction, including deficits in long-term potentiation (LTP), occurs before the appearance of plaques and tangles.

2. Cognition/Behavior: Cognitive impairments can be observed at 4 months of age. The impairments initially manifest as a deficit in retention/retrieval, rather than a lack of learning, and occur prior to the formation of plaques and tangles. These deficits in performance are evident in spatial and contextual-based paradigms. At 6.5 months of age, 3xTg mice show learning and memory deficits in the Barnes maze, but perform better than B6129SF2 wild-type mice in the Y-maze and fear conditioning tests. Immunotherapy that clears intracellular Aβ from neurons helps to restore hippocampal-dependent early cognitive deficits.

3xTg-AD Mice Applications

1. A widely used class of mouse models for familial Alzheimer's disease.

References

1. Oddo S, Caccamo A, Shepherd JD, et al. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003, 39(3):409-421.

2. Billings LM, Oddo S, Green KN, et al. Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron. 2005, 45(5):675-688.

3. Stover KR, Campbell MA, Van Winssen CM, et al. Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer's disease. Behav Brain Res. 2015, 289:29-38.