Research Models

APPPS1

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Species: Mouse
Genes: APP, PSEN1
Mutations: APP KM670/671NL (Swedish), PSEN1 L166P
Modification: APP: Transgenic; PSEN1: Transgenic;
Disease Relevance: Alzheimer's Disease
Strain Name: B6-Tg(Thy1-APPswe; Thy1-PS1 L166P)
Genetic Background: C57BL/6J
Availability: Available through Mathias Jucker

Modification Details

Human transgenes APP KM670/671NL and PSEN1 L166P, both under the control of the Thy1 promoter. Integration site is on lower arm of chromosome 2 between 40 and 60 cm.

Summary

APPPS1 mice contain human transgenes for both APP bearing the Swedish mutation and PSEN1 containing an L166P mutation, both under the control of the Thy1 promoter. In these mice, expression of human APP transgene is approximately 3-fold that of endogenous murine APP. The generation of human Aβ42 is higher than Aβ40, and both levels increase with age, but the ratio of brain Aβ42/40 decreases with the onset of amyloid deposition (Radde et al., 2006; Maia et al., 2013). Amyloid plaque deposition starts at approximately six weeks of age in the neocortex. Amyloid deposits in the hippocampus appears at 3-4 months, and in the striatum, thalamus and brainstem at 4-5 months. Phosphorylated tau-positive neuritic processes have been observed in the vicinity of all congophilic amyloid deposits, but no fibrillar tau inclusions are seen.

The CSF levels of Aβ and tau have also been extensively examined in these mice (Maia et al., 2013). Aβ42 concentrations in CSF of these mice decrease with age, with a 50 percent reduction by six months of age and an 80 percent reduction by 18 months. Aβ40 concentrations also decrease, but less dramatically (45 percent by 18 months). CSF concentrations of total tau increase in these animals, starting at six months and reaching a 5-fold increase by 18 months of age. 

The first publication characterizing these mice reported that they exhibited impaired reversal learning of a food-rewarded four-arm spatial maze task at eight months of age (Radde et al., 2006). Others have subsequently reported earlier observations of cognitive impairment, including deficits in the Morris Water maze at seven months of age (Serneels et al., 2009). Impairments in LTP in the hippocampal CA1 region have also been reported to start around this age (Gengler et al., 2010).

Global neuronal loss is not observed in APPPS1 mice, but modest neuron loss was found in the granule cell layer of the dentate gyrus and other subregions with high neuron density at older ages, e.g. 17 months (Rupp et al., 2011).

Phenotype Timeline

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Observed

Absent

  • Tangles

Unknown

Plaques

Aβ deposition begins at 6 weeks of age in the cortex and 3-4 months of age in the hippocampus (Radde et al., 2006).

Tangles

Phosphorylated tau-positive neuritic processes around plaques have been observed, but no mature tangles (Radde et al., 2006).

Neuronal Loss

Global neuron loss is not observed, but modest neuron loss was found in the granule cell layer of the dentate gyrus and other subregions with high neuronal density in 17-month old animals (Rupp et al., 2011).

Gliosis

Activated microglia around Aβ deposits at 6 weeks as well as increased astrogliosis (Radde et al., 2006). Levels of CCL2 and TNFα increase at later ages (Lee et al., 2010).

Synaptic Loss

Dendritic spine loss around plaques reported to begin approximately 4 weeks after plaque formation and continue for several months (Bittner et al., 2012).

Changes in LTP/LTD

Hippocampal CA1 LTP normal at 4.5 months of age, but impaired at 8 and 15 months of age (Gengler et al., 2010).

Cognitive Impairment

Cognitive deficits in spatial learning and memory in the Morris water maze reported at 7 months (Serneels et al., 2009). Impaired reversal learning of a food-rewarded four-arm spatial maze task observed at 8 months (Radde et al., 2006).

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References

Paper Citations

  1. . Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 2006 Sep;7(9):940-6. PubMed.
  2. . Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci Transl Med. 2013 Jul 17;5(194):194re2. PubMed.
  3. . gamma-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer's disease. Science. 2009 May 1;324(5927):639-42. PubMed.
  4. . Synaptic plasticity in the hippocampus of a APP/PS1 mouse model of Alzheimer's disease is impaired in old but not young mice. PLoS One. 2010;5(3):e9764. PubMed.
  5. . Early onset amyloid lesions lead to severe neuritic abnormalities and local, but not global neuron loss in APPPS1 transgenic mice. Neurobiol Aging. 2011 Dec;32(12):2324.e1-6. PubMed.

Other Citations

  1. Mathias Jucker

Further Reading

News

  1. Cerebrospinal Fluid Tau Climbs in Aβ Mouse Models

Papers

  1. . CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer's disease mouse models. Am J Pathol. 2010 Nov;177(5):2549-62. PubMed.
  2. . Amyloid plaque formation precedes dendritic spine loss. Acta Neuropathol. 2012 Dec;124(6):797-807. PubMed.
  3. . Early Enriched Environment Exposure Protects Spatial Memory and Accelerates Amyloid Plaque Formation in APP(Swe)/PS1(L166P) Mice. PLoS One. 2013;8(7):e69381. PubMed.