APPswe/PSEN1dE9 (line 85)
Synonyms: APP/PS1, APPswe/PS1deltaE9, line 85, APP(swe) + PSEN1DeltaE9, APPdE9, Borchelt mice
Genes: APP, PSEN1
Mutations: APP K670_M671delinsNL (Swedish), PSEN1: deltaE9
Modification: APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax
Genetic Background: C57BL/6;C3H
Availability: The Jackson Lab; available through the JAX MMRRC Stock# 034829 (formerly Jackson Lab Stock # 004462); Live
These transgenic mice were made by co-injecting two vectors encoding mutant APP and mutant PSEN1, respectively. Like the APPSwe/PSEN1dE9 mice generated by crossing transgenic APP animals with those expressing PSEN1dE9, these mice begin to develop Aβ deposits by six months of age, with abundant plaques in the hippocampus and cortex by nine months (Jankowsky et al., 2004). Plaques continue to increase up to around 12 months of age (Garcia-Alloza et al., 2006). Astrocytosis develops in parallel with plaque deposition, with severe gliosis starting around six months, especially in the vicinity of plaques. The number of GFAP-positive cells progressively increases with age, with extensive staining throughout the cortex by 15 months (Kamphuis et al., 2012). Between eight and 10 months, modest neuronal loss was observed adjacent to plaques relative to more distal areas (Jackson et al., 2016). Tangles are not typical in these animals.
The behavior of these mice has been well-characterized. Deficits have been reported across cognitive domains, although severity and timing depend on the specific behavioral protocols used (Janus et al., 2015). Contextual memory may be impaired as early as six months of age, as shown by freezing behavior in fear-conditioning tests (Kilgore et al., 2010). Spatial learning is comparable to non-Tg mice at seven months of age, but impaired by 12 months as measured by performance in the Morris water maze (Lalonde et al., 2005; Volianskis et al., 2010). Spontaneous behavior, such as nest-building and burrowing, is also affected (Janus et al., 2015).
Deficits in synaptic plasticity have been observed. Specifically, deficits in transient long-term potentiation (t-LTP) have been observed by three months, although the degree of impairment is not related to age from three to 12 months (Volianskis et al., 2010).
This line, on the hybrid C57BL/6 x C3H background, does not exhibit a seizure phenotype or carry the retinal degeneration allele Pde6brd1.
APPswe/PSEN1dE9 mice have been made on several genetic backgrounds (see related strains below).
These transgenic mice were made by co-injecting two vectors encoding mutant APP and mutant PSEN1. The APP sequence encodes a chimeric mouse/human APP (Mo/HuAPP695swe) that was “humanized” by modifying three amino acids. In addition, the mutations necessary for the Swedish mutation were introduced. The PSEN1 sequence encodes human presenilin-1 lacking exon 9 (dE9), which therefore models AD-associated mutations in PSEN1 resulting in exclusion of exon 9, variously known as ΔE9, dE9, deltaE9, Δ9, or delE9. Expression of both genes was directed to the CNS with the mouse prion protein promoter. The transgenes inserted at a single locus, Chr9:113003660 (Build GRCm38/mm10), causing a 1 bp duplication that does not affect any known genes (Goodwin et al., 2019).
APPswe/PSEN1dE9 (C57BL6). These mice are on a congenic C57/BL genetic background. They are available as JAX MMRRC Stock# 034832 (formerly as Jackson Lab Stock# 005864). A substantial proportion of these mice exhibit seizure activity.
D2.APBTg. These mice are on a D2 genetic background. They were generated by backcrossing B6.APBTg mice to stock D2 mice (DBA/2J; JAX Stock #000671). Mice on this background are more prone to spontaneous seizures than the B6 congenic. The seizures are lethal, and are thought to account for the premature death of D2.ABPTg mice; 70 percent die between two and three months of age. Those that survive to six months of age exhibit reduced amyloid pathology relative to B6 counterparts (Jackson et al., 2015).
CAST.APPPS1. These mice are among a set of three models created by backcrossing APPswe/PSEN1dE9 mice to different “wild-derived” strains—inbred strains created in the laboratory from subspecies of house mice caught in the wild less than 50 years ago (Onos et al., 2019). The CAST strain differs from C57BL6 at around 23 million sites in the genome. Compared with APPswe/PSEN1dE9 on a congenic C57BL/6J background, these mice are hyperactive and have fewer plaques, but more microglia surrounding each plaque. These mice also exhibit cerebral amyloid angiopathy. At 8 months, transgenic mice have fewer neurons in the hippocampus than do non-transgenic littermates, but whether this difference reflects a developmental problem or neurodegeneration has yet to be determined. Cognitive deficits are observed by 8 months in males.
WSB.APPPS1. This is the second line created by backcrossing APPswe/PSEN1dE9 mice to a “wild-derived” strain (Onos et al., 2019). The WSB strain differs from C57BL6 at around 7 million sites in the genome. Compared with APPswe/PSEN1dE9 on a congenic C57BL/6J background, these mice are hyperactive and have fewer plaques. These mice also exhibit cerebral amyloid angiopathy, with a compromised blood-brain barrier. Transgenic females have fewer neurons in the cortex and hippocampus than do non-transgenic littermates, but whether this difference reflects a developmental problem or neurodegeneration has yet to be determined. Cognitive deficits are observed by 8 months in females.
PWK.APP/PS1. This is the third of the lines created by backcrossing APPswe/PSEN1dE9 mice to a “wild-derived” strain (Onos et al., 2019). The PWK strain differs from C57BL6 at around 22 million sites in the genome. Compared with APPswe/PSEN1dE9 on a congenic C57BL/6J background, these mice are hyperactive and have fewer plaques. Neuron loss is not observed in cortex or hippocampus at 8 months. Working memory and short-term memory were intact at 6 to 8 months.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
Occasional Aβ deposits can be found by 6 months, with abundant plaques in the hippocampus and cortex by 9 months (Jankowsky et al., 2004) and a progressive increase in plaques up to 12 months (Garcia-Alloza et al., 2006).
Neuronal loss observed adjacent to plaques relative to more distal areas.
Minimal astrocytosis at 3 months; significant astrocytosis by 6 months, especially in areas around plaques. Extensive GFAP+ staining at 15 months and later throughout the cortex (Kamphuis et al., 2012).
In the B6 congenic mice, age-dependent loss of synaptophysin, synaptotagmin, PSD-95, and Homer immunoreactivity in the hippocampus by 4 months (Hong et al., 2016).
Changes in LTP/LTD
Transient long-term potentiation (t-LTP) is reduced by 3 months. The degree of impairment is not related to age from 3 to 12 months (Volianskis et al., 2008).
Impairment in the Morris water maze at 12 months, specifically during acquisition of the hidden platform sub-task and the probe trial, but not in the visible platform test (Lalonde et al., 2005). At 13 months the mice commit more errors in the Morris water maze, but not at 7 months (Volianskis et al., 2008).
Last Updated: 08 Oct 2019
Research Models Citations
- Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet. 2004 Jan 15;13(2):159-70. Epub 2003 Nov 25 PubMed.
- Garcia-Alloza M, Robbins EM, Zhang-Nunes SX, Purcell SM, Betensky RA, Raju S, Prada C, Greenberg SM, Bacskai BJ, Frosch MP. Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis. 2006 Dec;24(3):516-24. Epub 2006 Oct 5 PubMed.
- Kamphuis W, Mamber C, Moeton M, Kooijman L, Sluijs JA, Jansen AH, Verveer M, de Groot LR, Smith VD, Rangarajan S, Rodríguez JJ, Orre M, Hol EM. GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS One. 2012;7(8):e42823. Epub 2012 Aug 13 PubMed.
- Jackson RJ, Rudinskiy N, Herrmann AG, Croft S, Kim JM, Petrova V, Ramos-Rodriguez JJ, Pitstick R, Wegmann S, Garcia-Alloza M, Carlson GA, Hyman BT, Spires-Jones TL. Human tau increases amyloid β plaque size but not amyloid β-mediated synapse loss in a novel mouse model of Alzheimer's disease. Eur J Neurosci. 2016 Dec;44(12):3056-3066. Epub 2016 Nov 12 PubMed.
- Janus C, Flores AY, Xu G, Borchelt DR. Behavioral abnormalities in APPSwe/PS1dE9 mouse model of AD-like pathology: comparative analysis across multiple behavioral domains. Neurobiol Aging. 2015 Sep;36(9):2519-32. Epub 2015 May 21 PubMed.
- Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, Rumbaugh G. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology. 2010 Mar;35(4):870-80. PubMed.
- Lalonde R, Kim HD, Maxwell JA, Fukuchi K. Exploratory activity and spatial learning in 12-month-old APP(695)SWE/co+PS1/DeltaE9 mice with amyloid plaques. Neurosci Lett. 2005 Dec 23;390(2):87-92. PubMed.
- Volianskis A, Køstner R, Mølgaard M, Hass S, Jensen MS. Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe/PS1δE9-deleted transgenic mice model of ß-amyloidosis. Neurobiol Aging. 2010 Jul;31(7):1173-87. Epub 2008 Sep 13 PubMed.
- Goodwin LO, Splinter E, Davis TL, Urban R, He H, Braun RE, Chesler EJ, Kumar V, van Min M, Ndukum J, Philip VM, Reinholdt LG, Svenson K, White JK, Sasner M, Lutz C, Murray SA. Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis. Genome Res. 2019 Mar;29(3):494-505. Epub 2019 Jan 18 PubMed.
- Jackson HM, Onos KD, Pepper KW, Graham LC, Akeson EC, Byers C, Reinholdt LG, Frankel WN, Howell GR. DBA/2J genetic background exacerbates spontaneous lethal seizures but lessens amyloid deposition in a mouse model of Alzheimer's disease. PLoS One. 2015;10(5):e0125897. Epub 2015 May 1 PubMed.
- Onos KD, Uyar A, Keezer KJ, Jackson HM, Preuss C, Acklin CJ, O'Rourke R, Buchanan R, Cossette TL, Sukoff Rizzo SJ, Soto I, Carter GW, Howell GR. Enhancing face validity of mouse models of Alzheimer's disease with natural genetic variation. PLoS Genet. 2019 May;15(5):e1008155. Epub 2019 May 31 PubMed.
- Xiao Z, Cilz NI, Kurada L, Hu B, Yang C, Wada E, Combs CK, Porter JE, Lesage F, Lei S. Activation of neurotensin receptor 1 facilitates neuronal excitability and spatial learning and memory in the entorhinal cortex: beneficial actions in an Alzheimer's disease model. J Neurosci. 2014 May 14;34(20):7027-42. PubMed.
- Maroof N, Ravipati S, Pardon MC, Barrett DA, Kendall DA. Reductions in endocannabinoid levels and enhanced coupling of cannabinoid receptors in the striatum are accompanied by cognitive impairments in the AβPPswe/PS1ΔE9 mouse model of Alzheimer's disease. J Alzheimers Dis. 2014;42(1):227-45. PubMed.
- François A, Rioux Bilan A, Quellard N, Fernandez B, Janet T, Chassaing D, Paccalin M, Terro F, Page G. Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 transgenic mice. J Neuroinflammation. 2014 Aug 27;11:139. PubMed.
- Kemppainen S, Hämäläinen E, Miettinen PO, Koistinaho J, Tanila H. Behavioral and neuropathological consequences of transient global ischemia in APP/PS1 Alzheimer model mice. Behav Brain Res. 2014 Dec 15;275:15-26. Epub 2014 Sep 1 PubMed.
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