Research Models

Tg2576

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

Tools

Back to the Top

Species: Mouse
Genes: APP
Mutations: APP K670_M671delinsNL (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. Charles River, PsychoGenics, and Scantox Neuro offer research services with this line.

Summary

The Tg2576 model is one of the most well characterized, and widely used, mouse models of AD. It overexpresses a mutant form of APP (isoform 695) with the Swedish mutation (KM670/671NL), resulting in elevated levels of Aβ and ultimately amyloid plaques. The Tg2576 model was developed by Karen Hsiao Ashe and is now distributed through Taconic and Charles River. Hemizygous mice develop extensive amyloid pathology and cognitive deficits (Hsiao et al., 1996).

Tg2576 mice develop normally but exhibit age-associated cognitive deficits. Some reports have shown that the mice have impaired spatial learning and deficits in working memory and contextual fear conditioning at less than six months of age. Other studies have reported normal cognition at this age with progressive impairment at 12 months. Note, Tg2576 mice on this background carrying the Pde6brd1 retinal degeneration allele may develop light sensitivity and/or blindness which can effect the results of behavioral testing.

By 11-13 months of age, hemizygous mice develop numerous parenchymal Aβ plaques along with some vascular amyloid. They also show oxidative lipid damage but no evidence of neurofibrillary tangles or neuronal loss (Irizarry et al., 1997). Dendritic spine loss has been reported by 4.5 months in the CA1 region of the hippocampus (Lanz et al., 2003).

Changes in synaptic plasticity have been noted in the Tg2576 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).

One of the earliest signs of impairment may be neuronal hyperexcitability (Kam et al., 2016).

Modification Details

The Tg2576 model overexpresses human APP (isoform 695) containing the double mutation K670N, M671L (Swedish mutation) under the control of the hamster prion protein promoter.

Availability

Male and female mice are available through Taconic (Stock #1349) including mice aged up to 42 weeks. Charles River, PsychoGenics, and Scantox Neuro offer research services with this strain.

Related Strains

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. This strain was formerly available from Taconic as model #2789. Interested researchers should contact Taconic to request cryorecovery.

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

  • Tangles
  • Neuronal Loss

No Data

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.

Last Updated: 18 Jun 2024

COMMENTS / QUESTIONS

No Available Comments

Make a comment or submit a question

To make a comment you must login or register.

References

Paper Citations

  1. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996 Oct 4;274(5284):99-102. PubMed.
  2. Irizarry MC, McNamara M, Fedorchak K, Hsiao K, Hyman BT. APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neurol. 1997 Sep;56(9):965-73. PubMed.
  3. Lanz TA, Carter DB, Merchant KM. Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype. Neurobiol Dis. 2003 Aug;13(3):246-53. PubMed.
  4. Jacobsen JS, Wu CC, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE. 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.
  5. Chapman PF, White GL, Jones MW, Cooper-Blacketer D, Marshall VJ, Irizarry M, Younkin L, Good MA, Bliss TV, Hyman BT, Younkin SG, Hsiao KK. Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci. 1999 Mar;2(3):271-6. PubMed.
  6. Jung JH, An K, Kwon OB, Kim HS, Kim JH. Pathway-specific alteration of synaptic plasticity in Tg2576 mice. Mol Cells. 2011 Aug;32(2):197-201. Epub 2011 Jun 1 PubMed.
  7. Kam K, Duffy ÁM, Moretto J, LaFrancois JJ, Scharfman HE. Interictal spikes during sleep are an early defect in the Tg2576 mouse model of β-amyloid neuropathology. Sci Rep. 2016 Jan 28;6:20119. PubMed.

External Citations

  1. Taconic (Stock #1349)
  2. Charles River
  3. PsychoGenics
  4. Scantox Neuro
  5. Taconic: Stock #1349
  6. Charles River
  7. PsychoGenics
  8. Scantox Neuro

Further Reading

Papers

  1. Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, Bacskai BJ, Hyman BT. 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. McGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C, Skipper L, Murphy MP, Beard J, Das P, Jansen K, DeLucia M, Lin WL, Dolios G, Wang R, Eckman CB, Dickson DW, Hutton M, Hardy J, Golde T. Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron. 2005 Jul 21;47(2):191-199. PubMed.
  3. Wu ZL, Ciallella JR, Flood DG, O'Kane TM, Bozyczko-Coyne D, Savage MJ. Comparative analysis of cortical gene expression in mouse models of Alzheimer's disease. Neurobiol Aging. 2006 Mar;27(3):377-86. PubMed.
  4. Fonseca MI, Zhou J, Botto M, Tenner AJ. 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. Wilcock DM, Rojiani A, Rosenthal A, Levkowitz G, Subbarao S, Alamed J, Wilson D, Wilson N, Freeman MJ, Gordon MN, Morgan D. 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. Stern EA, Bacskai BJ, Hickey GA, Attenello FJ, Lombardo JA, Hyman BT. Cortical synaptic integration in vivo is disrupted by amyloid-beta plaques. J Neurosci. 2004 May 12;24(19):4535-40. PubMed.
  7. Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, Carlson GA, Younkin SG, Ashe KH. 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. Gau JT, Steinhilb ML, Kao TC, D'Amato CJ, Gaut JR, Frey KA, Turner RS. 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. Durk MR, Han K, Chow EC, Ahrens R, Henderson JT, Fraser PE, Pang KS. 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. Caccamo A, De Pinto V, Messina A, Branca C, Oddo S. 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.
  11. Duffy AM, Morales-Corraliza J, Bermudez-Hernandez KM, Schaner MJ, Magagna-Poveda A, Mathews PM, Scharfman HE. Entorhinal cortical defects in Tg2576 mice are present as early as 2-4 months of age. Neurobiol Aging. 2015 Jan;36(1):134-48. Epub 2014 Jul 11 PubMed.
  12. Rodriguez-Vieitez E, Ni R, Gulyás B, Tóth M, Häggkvist J, Halldin C, Voytenko L, Marutle A, Nordberg A. Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study. Eur J Nucl Med Mol Imaging. 2015 Jun;42(7):1119-32. Epub 2015 Apr 17 PubMed.
  13. Kam K, Duffy ÁM, Moretto J, LaFrancois JJ, Scharfman HE. Interictal spikes during sleep are an early defect in the Tg2576 mouse model of β-amyloid neuropathology. Sci Rep. 2016 Jan 28;6:20119. PubMed.