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
This popular model overexpresses human APP with two mutations linked to familial Alzheimer's disease (the Swedish and Indiana mutations). In this model APP 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. Compared with mice expressing an equivalent level of wild-type human APP, J20 mice have higher Aβ levels (Mucke et al., 2000). They exhibit an age-dependent increase in neuronal Aβ throughout the hippocampus between six and 36 weeks. In contrast to mice expressing wild-type APP, J20 mice develop plaques, typically by 5-7 months (Mucke et al., 2000). Hippocampal oligomeric Aβ expression also increases in an age-dependent manner, with significant increases observed by 36 weeks. Cell loss is variable. No significant neuronal loss was observed in the CA3 region of the hippocampus up to 36 weeks of age. Likewise, no significant cell loss was detected in the CA1 region at six weeks, but at 12, 24, and 36 weeks mice showed significant neuronal loss compared to aged-matched wild-type animals (Wright et al., 2013).
Deficits in spatial memory and learning appear as the mice age. As early as 16 weeks, J20 mice demonstrate spatial reference memory deficits as measured by the radial arm maze (Wright et al., 2013). By 6-7 months, deficits in spatial memory retention and acquisition in the water maze are observed (Palop et al., 2003).
Changes in synaptic plasticity are also observed. J20 mice between the ages of 3 and 6 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).
Note: This model was previously available at The Jackson Lab as Stock# 006293. A related line, formerly available through the Jackson Lab (Stock# 004661), is now extinct.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
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.
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).
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).
Age-dependent loss of synaptophysin immunoreactivity in presynaptic terminals is observed by 8-10 months, but does not correlate with plaque load (Mucke et al., 2000).
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).
Deficits in spatial memory and learning appear as the mice age. As early as 16 weeks mice demonstrate spatial reference memory deficits as measured by the radial arm maze (Wright et al., 2013). By 6-7 months deficits appear in spatial memory retention and acquisition in the water maze (Palop et al., 2003).
- Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L. 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.
- Wright AL, Zinn R, Hohensinn B, Konen LM, Beynon SB, Tan RP, Clark IA, Abdipranoto A, Vissel B. 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.
- Palop JJ, Jones B, Kekonius L, Chin J, Yu GQ, Raber J, Masliah E, Mucke L. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9572-7. Epub 2003 Jul 24 PubMed.
- Saganich MJ, Schroeder BE, Galvan V, Bredesen DE, Koo EH, Heinemann SF. 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.
- Chin J, Palop JJ, Puoliväli J, Massaro C, Bien-Ly N, Gerstein H, Scearce-Levie K, Masliah E, Mucke L. 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.
- Fu Y, Rusznák Z, Kwok JB, Kim WS, Paxinos G. 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.