Research Models

mThy1-hAPP751 (Line 41)

Synonyms: hAPPSL, hAPP-SL, AβPP751, TASD41, mThy1-hAβPP751 Swe Lon (line 41), APP751SL, hAPPlon/swe line 41 , APP41

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Species: Mouse
Genes: APP
Mutations: APP KM670/671NL (Swedish), APP V717I (London)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: mThy1-hAβPP751 Swe Lon
Genetic Background: C57BL/6 x DBA
Availability: Available through Eliezer Masliah. A similar strain, APPSL, is available through QPS-Austria on a congenic C57BL/6 background.

Summary

These transgenic mice express mutant human APP with both the Swedish (K670N/M671L) and London (V717I) mutations. They develop age-associated amyloid plaques and cognitive impairment.

Neuropathology

These mice exhibit age-dependent increases in Aβ40 and Aβ42, with Aβ42 preferentially elevated. Increased soluble Aβ40 and Aβ42 levels in the brain starting at six months in addition to increased Aβ oligomers. Plaques appear at an early age, starting at three to six months in the frontal cortex. At five to seven months, dense amyloid deposits appear in hippocampous, thalamus, and olfactory region (Rockenstein et al., 2001). Increased Aβ plaque burden in cortex and hippocampus starting at three to four months; Increased astrocytosis and microgliosis starting at nine months; dystrophic neurites and synaptic loss starting at 12 months. Lipid peroxidation starting at nine months.

Cognition/Behavior

By six months of age these mice already show significant learning and memory deficits in the Morris water maze (Rockenstein et al., 2005). Even at advanced age, they do not develop appreciable motor impairment. Some sex-specific differences have been observed in open field exploration and thigmotaxis, the tendency to remain close to walls when exploring a new environment (Havas et al., 2011).

Modification Details

These transgenic mice express mutant human APP (isoform 751) bearing both the Swedish (K670N/M671L) and the London (V717I) mutations. The transgene is under the control of the murine Thy1 promoter.

Availability

Available through Eliezer Masliah.

Related Strains

APPSL mice carry the same genetic construct as mThy1-hAPP751 (Line 41) but are on a congenic C57BL/6 background. They have similar pathology and behavioral deficits, including progressive plaque deposition in the cortex and hippocampus along with cognitive impairment (Windisch et al., 2013). Their early plaque pathology and cognitive impairment not confounded by motor deficits, have contributed to their popularity as preclinical models (e.g. Hutter-Paier et al., 2004, Huttunen et al., 2010; and Imbimbo et al., 2009). APPSL mice are available as a live stock through QPS-Austria.

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

Plaques start at 3-6 months in the frontal cortex and become widespread with age, affecting the piriform and olfactory cortices, hippocampus, and thalamus (Rockenstein et al., 2001; Havas et al., 2011).

Tangles

Absent.

Gliosis

Inflammation related to activated microglia (increased CD11) and reactive astrocytes (increased GFAP) is significant by 6 months and increases with age.

Synaptic Loss

Dystrophic neurites and synaptic loss starting at 12 months.

Cognitive Impairment

Cognitive impairment observed by 6 months by Morris Water Maze (Rockenstein et al., 2005).

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References

Paper Citations

  1. . Early formation of mature amyloid-beta protein deposits in a mutant APP transgenic model depends on levels of Abeta(1-42). J Neurosci Res. 2001 Nov 15;66(4):573-82. PubMed.
  2. . High beta-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-beta levels: implications for the treatment of Alzheimer disease. J Biol Chem. 2005 Sep 23;280(38):32957-67. PubMed.
  3. . A longitudinal study of behavioral deficits in an AβPP transgenic mouse model of Alzheimer's disease. J Alzheimers Dis. 2011;25(2):231-43. PubMed.
  4. . Commentary to the recently published review "Drug pipeline in neurodegeneration based on transgenic mice models of Alzheimer's disease" by Li, Evrahimi and Schluesener. Ageing Res. Rev. 2013 Jan;12(1):116-40. Ageing Res Rev. 2013 Jul 10;12(4):852-854. PubMed.
  5. . The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease. Neuron. 2004 Oct 14;44(2):227-38. PubMed.
  6. . The acyl-coenzyme A: cholesterol acyltransferase inhibitor CI-1011 reverses diffuse brain amyloid pathology in aged amyloid precursor protein transgenic mice. J Neuropathol Exp Neurol. 2010 Aug;69(8):777-88. PubMed.
  7. . CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease. Br J Pharmacol. 2009 Mar;156(6):982-93. PubMed.

Other Citations

  1. Eliezer Masliah

Further Reading

Papers

  1. . Thy1-hAPP(Lond/Swe+) mouse model of Alzheimer's disease displays broad behavioral deficits in sensorimotor, cognitive and social function. Brain Behav. 2012 Mar;2(2):142-54. PubMed.
  2. . Effects of Cerebrolysin on amyloid-beta deposition in a transgenic model of Alzheimer's disease. J Neural Transm Suppl. 2002;(62):327-36. PubMed.
  3. . A neuroprotective brain-penetrating endopeptidase fusion protein ameliorates Alzheimer disease pathology and restores neurogenesis. J Biol Chem. 2014 Jun 20;289(25):17917-31. Epub 2014 May 13 PubMed.
  4. . High beta-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-beta levels: implications for the treatment of Alzheimer disease. J Biol Chem. 2005 Sep 23;280(38):32957-67. PubMed.
  5. . Peripheral delivery of a CNS targeted, metalo-protease reduces aβ toxicity in a mouse model of Alzheimer's disease. PLoS One. 2011;6(1):e16575. PubMed.
  6. . Neuropeptide Y fragments derived from neprilysin processing are neuroprotective in a transgenic model of Alzheimer's disease. J Neurosci. 2009 Jan 28;29(4):1115-25. PubMed.
  7. . Beneficial effects of a neurotrophic peptidergic mixture persist for a prolonged period following treatment interruption in a transgenic model of Alzheimer's disease. J Neurosci Res. 2011 Nov;89(11):1812-21. PubMed.
  8. . Neuroinflammation and related neuropathologies in APPSL mice: further value of this in vivo model of Alzheimer's disease. J Neuroinflammation. 2014 May 1;11:84. PubMed.