Genes: APOE, APP, PSEN1
Mutations: APP KM670/671NL (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. APOE2 Targeted Replacement mice are available through Taconic, Stock# 1547-F or 1547-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 with the APOE2 isoform had an increased percentage of diffuse plaques with a decrease in compact plaques relative to E4FAD mice. Plaque morphology was comparable between E2FAD and E3FAD animals. Generally, E3FAD mice also had greaters levels of APOE and less Aβ42 in the brain, relative to E4FAD animals. 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. E4FAD and E2FAD mice had increased numbers of microglia associated with plaques in the cortex.
In hippocampal lysates from female mice, synaptic protein levels were largely comparable between E3FAD and E2FAD mice, while protien levels were lower in E4FAD mice (Liu et al., 2015). Additionally, cognitive performance of female mice in the Y maze and Morris water maze showed similar trends, with E3FAD and E2FAD mice performing similarly, while E4FAD mice had greater imparments.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Changes in LTP/LTD
- Cognitive Impairment
Plaques develop in the subiculum and deep cortical layers by 4 months.
Microgliosis and astrocytosis in the subiculum and cortex at 6 months.
Protein levels of NMDA receptor subunits decreased from 2 to 6 months.
Changes in LTP/LTD
E2FAD mice had performance in learning and memory tasks comparable to E3FAD animals and better than E4FAD mice.
Research Models Citations
- 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.
- 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.
- 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.
No Available Further Reading