Research Models

J20 (PDGF-APPSw,Ind)

Synonyms: PDGF-hAPP695,751,770V171F, KM670/671NL, hAPPJ20, hAPP, Mucke mice

Species: Mouse
Genes: APP
Mutations: APP KM670/671NL (Swedish), APP V717F (Indiana)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Tg(PDGFB-APPSwInd)20Lms/2Mmjax
Genetic Background: C57BL/6
Availability: The Jackson Lab; available through the JAX MMRRC Stock# 034836; Live

Summary

This popular mouse model overexpresses human APP with two mutations linked to familial Alzheimer's disease (the Swedish and Indiana mutations). Transgene expression is driven by the PDGF-β promoter and immunoreactivity is detected in neurons throughout the brain with highest levels in the neocortex and hippocampus.

J20 mice have more Aβ than mice expressing equivalent amounts of wild-type human APP. Aβ levels in hippocampal neurons increase between six and 36 weeks of age.  J20 mice develop robust amyloid plaques by five to seven months of age (Mucke et al., 2000). No significant neuronal loss was observed in the CA3 region of the hippocampus up to 36 weeks of age compared to non-Tg mice. Likewise, in the CA1 region, neuronal numbers were intact at six weeks; but decreased at 12, 24, and 36 weeks of age (Wright et al., 2013). Elevated levels of complement proteins C1q and C3 were observed in the hippocampus and frontal cortex at one month of age. Additionally, C1q and C3 showed greater co-localization with PSD-95 puncta (Hong et al., 2016).

Deficits in spatial memory and learning appear as the mice age. By 4 months, J20 mice demonstrate spatial reference memory deficits as measured by the radial arm maze (Wright et al., 2013) and Morris water maze (Cheng et al., 2007).

Changes in synaptic plasticity are also observed. J20 mice between the ages of three and six months show deficits in basal synaptic transmission. Extracellularly recorded field EPSPs at the Schaffer collateral to CA1 synapse in acute hippocampal slices were on average smaller in amplitude than those seen in wild-type mice. J20 mice also had significant deficits in LTP at the Schaffer collateral–CA1 synapse compared with control mice at this age (Saganich et al., 2006).

The insertion site of the APP transgene has been mapped to mouse chromosome 16, within intron 1 of the ZBTB20 gene (Tosh et al., 2017). ZBTB20 is a transcriptional repressor that plays a role in hippocampal development (Mitchelmore et al., 2002). It has been reported that ZBTB20 mRNA expression in the hippocampus is reduced in young J2O mice compared with their non-transgenic littermates, but no difference was reported at the protein level (Tosh et al., 2017).  To what extent, if any, disruption of the ZBTB20 gene contributes to the development of the J20 phenotype awaits further study, including a thorough characterization of the gene's expression across development and adulthood in this model.

Note: This model was previously available at The Jackson Lab as Stock# 006293. A related line, formerly available through the Jackson Lab as Stock# 004661, is now extinct.

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

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Plaques

At 5-7 months of age diffuse amyloid-β plaques deposit in the dentate gyrus and neocortex. Amyloid deposition is progressive with widespread plaques by 8-10 months. Aβ puncta are deposited in the hippocampus as early as 1 month (Hong et al., 2016).

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Absent.

Neuronal Loss

Cell loss varies by brain region. No significant neuronal loss was observed in the CA3 region of the hippocampus at 6, 12, 24 and 36 weeks of age nor in the CA1 region at 6 weeks; however, at 12, 24, and 36 weeks significant neuronal loss was observed in the CA1 region compared to age-matched wild-type animals (Wright et al., 2013).

Gliosis

At 24 and 36 weeks a significant increase in the number of reactive GFAP+ astrocytes and CD68+ microglia was observed in the hippocampi of J20 mice compared to age-matched wild-type controls. No significant difference was observed at 6 and 12 weeks (Wright et al., 2013).

Synaptic Loss

Age-dependent loss of synaptophysin, synaptotagmin, PSD-95, and homer immunoreactivity in the hippocampus by 3 months; synapse loss was confirmed by electron microscopy. No significant difference was seen at 1 month (Hong et al., 2016).

Changes in LTP/LTD

Basal synaptic transmission is impaired between 3-6 months; extracellularly recorded field EPSPs at the Schaffer collateral to CA1 synapse in acute hippocampal slices were on average smaller in amplitude than those seen in wild-type mice. Significant deficits in LTP at the Schaffer collateral–CA1 synapse compared with control mice at 3-6 months (Saganich et al., 2006).

Cognitive Impairment

Deficits in spatial memory and learning appear as the mice age. By 4 months, J20 mice demonstrate spatial reference memory deficits as measured by the radial arm maze (Wright et al., 2013) and Morris water maze (Cheng et al., 2007).

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References

Paper Citations

  1. . High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci. 2000 Jun 1;20(11):4050-8. PubMed.
  2. . Neuroinflammation and neuronal loss precede Aβ plaque deposition in the hAPP-J20 mouse model of Alzheimer's disease. PLoS One. 2013;8(4):e59586. Epub 2013 Apr 1 PubMed.
  3. . Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 May 6;352(6286):712-6. Epub 2016 Mar 31 PubMed.
  4. . Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J Biol Chem. 2007 Aug 17;282(33):23818-28. PubMed.
  5. . Deficits in synaptic transmission and learning in amyloid precursor protein (APP) transgenic mice require C-terminal cleavage of APP. J Neurosci. 2006 Dec 27;26(52):13428-36. PubMed.
  6. . The integration site of the APP transgene in the J20 mouse model of Alzheimer's disease. Wellcome Open Res. 2017;2:84. Epub 2017 Sep 13 PubMed.
  7. . Characterization of two novel nuclear BTB/POZ domain zinc finger isoforms. Association with differentiation of hippocampal neurons, cerebellar granule cells, and macroglia. J Biol Chem. 2002 Mar 1;277(9):7598-609. Epub 2001 Dec 13 PubMed.

External Citations

  1. JAX MMRRC Stock# 034836

Further Reading

Papers

  1. . Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease. J Neurosci. 2005 Oct 19;25(42):9694-703. PubMed.
  2. . Age-dependent alterations of the hippocampal cell composition and proliferative potential in the hAβPPSwInd-J20 mouse. J Alzheimers Dis. 2014;41(4):1177-92. PubMed.