Research Models

E4FAD

Synonyms: APOE4-FAD, APOE4 Targeted Replacement x 5xFAD

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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

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

  • Tangles
  • Neuronal Loss
  • Changes in LTP/LTD

Plaques

Plaques develop in the subiculum and deep cortical layers by 4 months.

Tangles

No data.

Neuronal Loss

No data.

Gliosis

Microgliosis and astrocytosis in the subiculum and cortex at 6 months.

Synaptic Loss

Decreased protein levels of PSD95 and NMDA receptor subunits by 4 months.

Changes in LTP/LTD

No data.

Cognitive Impairment

Modest learning deficits in the Morris water maze by 2 months. Progressive decrease in performance on learning and memory tasks. 

Last Updated: 09 Jun 2017

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References

Research Models Citations

  1. APOE4 Targeted Replacement
  2. E3FAD
  3. E2FAD

Paper Citations

  1. . 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. . Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition. J Neuroinflammation. 2014 Jun 19;11:111. PubMed.
  3. . 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

Papers

  1. . Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition. J Neuroinflammation. 2014 Jun 19;11:111. PubMed.
  2. . 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.