Research Models

3xTg

Synonyms: 3xTg-AD, The LaFerla mouse

Tools

Back to the Top

Species: Mouse
Genes: Psen1, APP, MAPT
Mutations: APP K670_M671delinsNL (Swedish), MAPT P301L, PSEN1 M146V
Modification: Psen1: Knock-In; APP: Transgenic; MAPT: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6;129-Psen1tm1Mpm Tg(APPSwe,tauP301L)1Lfa/Mmjax
Genetic Background: C7BL/6;129X1/SvJ;129S1/Sv
Availability: The Jackson Lab; available through the JAX MMRRC Stock# 034830; Live

Summary

These widely-used mice contain three mutations associated with familial Alzheimer's disease (APP Swedish, MAPT P301L, and PSEN1 M146V). The mice are viable, fertile, and display no initial gross physical or behavioral abnormalities. Translation of the overexpressed transgenes appears restricted to the central nervous system, including the hippocampus and cerebral cortex. These mice display both plaque and tangle pathology. Aβ deposition is progressive, with intracellular immunoreactivity detected in some brain regions as early as three to four months of age. Extracellular Aβ deposits appear by six months in the frontal cortex and become more extensive by twelve months. Changes in tau occur later; by 12 to 15 months aggregates of conformationally-altered and hyperphosphorylated tau are detected in the hippocampus (Oddo et al., 2003; Billings et al., 2005).

Neuropathology

These mice develop age-related, progressive neuropathology including plaques and tangles. Extracellular Aβ deposits are apparent by six months in the frontal cortex, and become more extensive by twelve months. Although tau pathology is not observed at six months, it is evident by twelve months. Synaptic dysfunction, including LTP deficits, occur prior to plaques and tangles.

Cognition/Behavior

Cognitive impairment is observed by four months. Impairments first manifest as a retention/retrieval deficit and not as a learning deficit, and occur prior to plaques and tangles. Deficits are observed in both spatial and contextual based paradigms. At age 6.5 months, 3xTg mice displayed learning and memory deficits in the Barnes maze, but performed better than B6129SF2 wild-type mice in the Y maze and fear conditioning tasks (Stover et al., 2015). Clearance of intraneuronal Aβ by immunotherapy rescues the early cognitive deficits in a hippocampal-dependent task.

Modification Details

Single-cell embryos from mice with knock-in of PSEN1 with the PS1M146V mutation were injected with two human transgenes (APP with the Swedish mutation and MAPT with the P30IL mutation, both under the control of the mouse Thy1.2 promoter). The transgenes integrated at a single locus, Chr2:87862466-87862463 (Build GRCm38/mm10), causing a 3 bp deletion that does not affect any known genes (Goodwin et al., 2017).

Note

This model was formerly available through The Jackson Lab as Stock# 004807.

Related Strains

3xTg-AD mice on a C57BL/6J-congenic background. Strain B6.Cg-Tg(APPSwe,tauP301L)1Lfa Psen1tm1Mpm/2J. Available from The Jackson Laboratory, Stock No. 033930.

3xTg-AD mice on a B6;129 genetic background. Strain B6;129-Tg(APPSwe,tauP301L)1Lfa Psen1tm1Mpm/Mmjax. Available from The Jackson Laboratory, Stock No. 004807.

3xTg-AD mice on a 129S4 genetic background. Strain  129S4.Cg-Tg(APPSwe,tauP301L)1Lfa Psen1tm1Mpm/LfaJ. Available from The Jackson Laboratory, Stock No. 031988.

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

No Data

  • Neuronal Loss

Plaques

Extracellular Aβ deposits by 6 months in the frontal cortex, predominantly layers 4 and 5 and progress with age (Oddo et al., 2003).

Tangles

By 12 months extensive tau immunoreactivity in CA1 neurons of the hippocampus, particularly pyramidal neurons, later in the cortex. No tau pathology at 6 months (Oddo et al., 2003).

Neuronal Loss

Unknown.

Gliosis

Increased density of GFAP immunoreactive astrocytes and IBA-1 immunoreactive microglia compared with wild-type mice at 7 months (Caruso et al., 2013). Development of gliosis may occur earlier.

Changes in LTP/LTD

By 6 months decreased LTP compared with wild type controls. Impairment in basal synaptic transmission. No change at 1 month of age (Oddo et al., 2003).

Cognitive Impairment

Cognitive impairment manifests at 4 months as a deficit in long-term retention and correlates with the accumulation of intraneuronal Aβ in the hippocampus and amygdala, but plaques and tangles are not yet apparent (Billings et al., 2005).

Last Updated: 31 Oct 2023

COMMENTS / QUESTIONS

No Available Comments

Make a comment or submit a question

To make a comment you must login or register.

References

Paper Citations

  1. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21. PubMed.
  2. Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron. 2005 Mar 3;45(5):675-88. PubMed.
  3. Stover KR, Campbell MA, Van Winssen CM, Brown RE. Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer's disease. Behav Brain Res. 2015 Aug 1;289:29-38. Epub 2015 Apr 17 PubMed.
  4. Goodwin LO, Splinter E, Davis TL, Urban R, He H, Braun RE, Chesler EJ, Kumar V, van Min M, Ndukum J, Philip VM, Reinholdt LG, Svenson K, White JK, Sasner M, Lutz C, Murray SA. Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis. bioRχiv preprint first posted online Dec. 18, 2017

External Citations

  1. The Jackson Laboratory, Stock No. 033930
  2. The Jackson Laboratory, Stock No. 004807
  3. The Jackson Laboratory, Stock No. 031988
  4. JAX MMRRC Stock# 034830

Further Reading

Papers

  1. Blázquez G, Cañete T, Tobeña A, Giménez-Llort L, Fernández-Teruel A. Cognitive and emotional profiles of aged Alzheimer's disease (3×TgAD) mice: effects of environmental enrichment and sexual dimorphism. Behav Brain Res. 2014 Jul 15;268:185-201. Epub 2014 Apr 15 PubMed.
  2. Martin SA, Jameson CH, Allan SM, Lawrence CB. Maternal high-fat diet worsens memory deficits in the triple-transgenic (3xTgAD) mouse model of Alzheimer's disease. PLoS One. 2014;9(6):e99226. Epub 2014 Jun 11 PubMed.
  3. Torres-Lista V, López-Pousa S, Giménez-Llort L. Marble-burying is enhanced in 3xTg-AD mice, can be reversed by risperidone and it is modulable by handling. Behav Processes. 2015 Jul;116:69-74. Epub 2015 May 6 PubMed.