Research Models

Tg2576

Synonyms: Hsiao mice, App-Swe, App-sw, APP(sw)

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Species: Mouse
Genes: APP
Mutations: APP KM670/671NL (Swedish)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6;SJL-Tg(APPSWE)2576Kha
Genetic Background: B6;SJL Mixed Background
Availability: Taconic Stock #1349 and Charles River Tg2576

Summary

Tg2576 mice overexpress a mutant form of APP (isoform 695) bearing the Swedish mutation (KM670/671NL). This model was originally developed by Karen Hsiao Ashe and are now maintained at Taconic and Charles River. The mice develop numerous parenchymal Aβ plaques by 11-13 months with some vascular amyloid. They also show oxidative lipid damage but no evidence of neurofibrillary tangles. Cognitive function has been extensively characterized in this model. Impaired learning at a spatial task, working memory and contextual fear conditioning have been reported at less than six months although other studies have reported normal cognition at this age with progressive impairment at 12 months. Dendritic spine loss has been reported by 4.5 months in the CA1 region of the hippocampus.

Changes in synaptic plasticity have been noted in this model. By five months, there was a decline in LTP in the dentate gyrus after perforant path stimulation compared to wild-type animals. No deficit was observed at two months (Jacobsen et al., 2006). LTP in both the CA1 and dentate gyrus of aged mice (greater than 15 months) is impaired (Chapman et al., 1999), but differences have been observed between the Schaffer collateral and mossy fiber pathways (Jung et al., 2011).

Modification Details

The human APP gene (isoform 695) containing the double mutation K670N, M671L (Swedish mutation) under the control of the hamster prion protein.

Related Strains

Taconic: Stock# 002789
This strain is on a 129S6 background. It does not carry the Pde6brd1 retinal degeneration allele, but as with all 129 substrains, does carry a mutated Disc1 gene.

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
  • Neuronal Loss

Unknown

Plaques

Numerous parenchymal Aβ plaques by 11-13 months.

Tangles

Absent.

Neuronal Loss

Absent or very limited.

Gliosis

Increase in microglial density and size in plaque-forming areas of the brain including the hippocampus, frontal cortex, entorhinal cortex, and occipital cortex in 10-16 month old hemizygotes (Frautschy et al., 1998).

Synaptic Loss

Dendritic spine loss by 4.5 months In the CA1 region of the hippocampus (Lanz et al., 2003).

Changes in LTP/LTD

By 5 months, there was a decline in LTP in the dentate gyrus after perforant path stimulation compared to wild-type; impairment was not observed at 2 months (Jacobsen et al., 2006). Both the CA1 and dentate gyrus of aged mice (>15 months) are impaired (Chapman et al., 1999). Differences have been observed between the Schaffer collateral and mossy fiber pathways (Jung et al., 2011).

Cognitive Impairment

Impaired spatial learning, working memory, and contextual fear conditioning at <6 months although other studies have reported normal cognition at this age with progressive impairment by >12 months.

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References

Paper Citations

  1. . Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5161-6. Epub 2006 Mar 20 PubMed.
  2. . Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci. 1999 Mar;2(3):271-6. PubMed.
  3. . Pathway-specific alteration of synaptic plasticity in Tg2576 mice. Mol Cells. 2011 Aug;32(2):197-201. Epub 2011 Jun 1 PubMed.

External Citations

  1. Taconic: Stock# 002789
  2. Taconic Stock #1349
  3. Charles River Tg2576

Further Reading

Papers

  1. . Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci. 2005 Aug 3;25(31):7278-87. PubMed.
  2. . Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron. 2005 Jul 21;47(2):191-9. PubMed.
  3. . Comparative analysis of cortical gene expression in mouse models of Alzheimer's disease. Neurobiol Aging. 2006 Mar;27(3):377-86. PubMed.
  4. . Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J Neurosci. 2004 Jul 21;24(29):6457-65. PubMed.
  5. . Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition. J Neurosci. 2004 Jul 7;24(27):6144-51. PubMed.
  6. . Cortical synaptic integration in vivo is disrupted by amyloid-beta plaques. J Neurosci. 2004 May 12;24(19):4535-40. PubMed.
  7. . The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease. J Neurosci. 2002 Mar 1;22(5):1858-67. PubMed.
  8. . Stable beta-secretase activity and presynaptic cholinergic markers during progressive central nervous system amyloidogenesis in Tg2576 mice. Am J Pathol. 2002 Feb;160(2):731-8. PubMed.
  9. . 1α,25-Dihydroxyvitamin D3 reduces cerebral amyloid-β accumulation and improves cognition in mouse models of Alzheimer's disease. J Neurosci. 2014 May 21;34(21):7091-101. PubMed.
  10. . Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer's disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature. J Neurosci. 2014 Jun 4;34(23):7988-98. PubMed.