Species: Mouse
Genes: APOE, APP, PSEN1
Mutations: APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V
Modification: APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL/6
Availability: 5xFAD mice are available through The Jackson Lab, Stock# 034840; Live. APOE4 Targeted Replacement mice are available through Taconic, Stock# 1549-F or 1549-M.

The E4FAD, E3FAD, and E2FAD mouse models are crosses between the widely used 5xFAD mice (Tg6799 line) and the APOE4, APOE3, and APOE2 Targeted Replacement mice, respectively. These models were created to study the role of the three human isoforms of APOE on AD phenotypes. The mice described here were homozygous for the APOE allele and heterozygous of the 5xFAD mutations. In general, the EFAD mice display less severe phenotypes relative to the 5xFAD line.

While the 5xFAD model rapidly developed plaques around two months, the EFAD mice developed plaques in the subiculum and the cortex at four months and the number of amyloid plaques increased with age (Youmans et al., 2012). At four and six months, E4FAD mice had significantly more plaques than the E3FAD and E2FAD models. At six months, the E2FAD mice exhibited a greater plaque load relative to E3FAD animals. The brains of mice expressing APOE4 had an increased percentage of compact plaques with a decrease in diffuse plaques relative to E3FAD and E2FAD mice. Generally, E4FAD mice also had reduced brain levels of APOE4 and increased Aβ42 levels. Male mice were used to assess neuropathology.

All EFAD mice showed microgliosis and astrocytosis at six months of age in the subiculum and cortex (Rodriguez et al., 2014). In the subiculum, microgliosis was comparable between mice with different APOE isoforms. The E4FAD and E2FAD mice had increased numbers of microglia associated with plaques in the cortex.

In hippocampal lysates from female mice, synaptophysin protein levels were not decreased between two and six months, nor were there differences between mice with different APOE isoforms (Liu et al., 2015).  PSD95 levels remained constant up to six months in E2FAD mice, while levels decreased by four months and six months in E4FAD mice and E3FAD mice, respectively. Additionally, NMDAR1, NMDAR2A, and NMDAR2B levels decreased over time, with the greatest reductions in E4FAD mice, intermediate changes in E3FAD mice, and the smallest reductions in E2FAD mice.

Cognitive performance of female mice in the Y maze and Morris water maze showed similar trends to isoform-specific changes in synapse proteins (Liu et al., 2015). Specifically, E4FAD mice exhibited the greatest age-dependent deficits relative to E3FAD and E2FAD animals.

Related Strains:

APOE4 Targeted Replacement

5xFAD

E3FAD

E2FAD

Phenotype Characterization

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References

Research Models Citations

1. APOE4 Targeted Replacement
2. E3FAD
3. E2FAD

Paper Citations

1. Youmans KL, Tai LM, Nwabuisi-Heath E, Jungbauer L, Kanekiyo T, Gan M, Kim J, Eimer WA, Estus S, Rebeck GW, Weeber EJ, Bu G, Yu C, LaDu MJ. APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease. J Biol Chem. 2012 Dec 7;287(50):41774-86. PubMed.
2. Rodriguez GA, Tai LM, LaDu MJ, Rebeck GW. Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition. J Neuroinflammation. 2014 Jun 19;11:111. PubMed.
3. Liu DS, Pan XD, Zhang J, Shen H, Collins NC, Cole AM, Koster KP, Ben Aissa M, Dai XM, Zhou M, Tai LM, Zhu YG, LaDu M, Chen XC. APOE4 enhances age-dependent decline in cognitive function by down-regulating an NMDA receptor pathway in EFAD-Tg mice. Mol Neurodegener. 2015 Mar 5;10:7. PubMed.

Other Citations

1. 5xFAD

External Citations

1. The Jackson Lab, Stock# 034840
2. Taconic, Stock# 1549-F or 1549-M

Further Reading