Research Models

TgCRND8

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Species: Mouse
Genes: APP
Mutations: APP KM670/671NL (Swedish), APP V717F (Indiana)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: Hybrid C3H/He-C57BL/6
Availability: Available through the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto

Modification Details

Transgene contains human APP695 with the Swedish mutation (KM670/671/NL) and Indiana mutation (V717F) under the control of the hamster prion (PrP) gene promoter. The expression cassette includes about 90 nucleotides of the APP 5'-untranslated region adjacent to the start codon and 269 nucleotides of the 3′-untranslated region.

Summary

This transgenic line over-expresses mutant human APP at levels approximately 5-fold higher than endogenous murine APP. Both human Aβ40 and Aβ42 are produced and increase with age, with Aβ42 being the more prevalent species (Chishti et al., 2001). These mice develop early plaque formation with thioflavine S-positive amyloid deposits observed at 3 months and dense cored plaques with neuritic pathology by 5 months, becoming more extensive with advanced age. Activated microglia appear concurrently with plaques and GFAP-positive astrocytes follow later, starting about 13-14 weeks (Dudal et al., 2004). Dystrophic neurites are also observed (Dudal et al., 2004; Woodhouse et al., 2009) along with cholinergic dysfunction, including a decrease in the number of cholinergic neurons in the nucleus basalis magnocellularis as measured by ChAT immunoreactivity (Bellucci et al., 2006).

Behaviorally these mice show a variety of impairments, including early impairment in acquisition and learning reversal in the reference memory version of the Morris water maze, by 3 months of age (Chishti et al., 2001). Age-associated cognitive deficits are observed in the step-down inhibitory avoidance test  (deficits at 7 months, but not at 2 months). No differences from wild-type mice were observed in motility, exploratory activity, or neuromuscular function at 7 months as evaluated by the rotarod, hole board and grip strength tests (Bellucci et al., 2006).

Survival rates depend on the genetic background. Survival on the (C57) × (C3H/C57) genetic background was the highest, with 50 percent of mice surviving until postnatal day 365 (the upper limit in the analysis. Mice on the (C3H/C57/129SvEv/Tac) × (129SvEv/Tac) and (FVB)×(C3H/C57) had increased mortality with 25 percent and 17 percent respectively reaching 365 days (Chishti et al., 2001).

Immunization against Aβ42 reduced both deposition of cerebral fibrillar Aβ and cognitive dysfunction (Janus et al., 2000).

Availability

Available through the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto (crnd.info@utoronto.ca).

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

Amyloid deposition progresses with age. Thioflavine S-positive amyloid deposits at 3 months; dense cored plaques and neuritic pathology by 5 months. Plaques appear first in the subiculum, amygdala and frontal cortex, spread to the dentate gyrus, the olfactory bulb, and later thalamus, cerebral vasculature, and striatum, followed by the cerebellum and brain stem (Chishti et al., 2001).

Tangles

Neurofibrillary tangles are absent (Chishti et al., 2001). Tau is hyperphosphorylated, nitrosylated and aggregated at 7-12 months especially in the neocortex, dentate gyrus, and the CA1 and CA3 areas of the hippocampus (Bellucci et al., 2007).

Neuronal Loss

Variable cell loss by region. No difference in overall cell count, but fewer hippocampal neurons at 6 months (Brautigam et al., 2012).

Gliosis

Microglia activation appears simultaneously with Aβ deposition, with only rare activated microglia at 9-10 weeks, but by 13-14 weeks microglia cluster around Aβ deposits in the cerebral cortex and hippocampus; numerous by 20 weeks. Robust astrogliosis slightly later with clusters of GFAP+ astrocytes emerging around plaques at 13-14 weeks (Dudal et al., 2004).

Synaptic Loss

Reduced synaptophysin immunoreactivity in the vicinity of plaques at 6 months (Adalbert et al., 2009).

Changes in LTP/LTD

In hippocampal slices from 6- to 12-month-old mice basal excitatory synaptic transmission (as assessed by I/O relationships) and LTP at CA1 are reduced in TgCRND8 mice compared with wild-type mice (Kimura et al., 2012).

Cognitive Impairment

Early impairment in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months (Chishti et al., 2001).

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References

Paper Citations

  1. . Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem. 2001 Jun 15;276(24):21562-70. PubMed.
  2. . Inflammation occurs early during the Abeta deposition process in TgCRND8 mice. Neurobiol Aging. 2004 Aug;25(7):861-71. PubMed.
  3. . Dystrophic neurites in TgCRND8 and Tg2576 mice mimic human pathological brain aging. Neurobiol Aging. 2009 Jun;30(6):864-74. PubMed.
  4. . Cholinergic dysfunction, neuronal damage and axonal loss in TgCRND8 mice. Neurobiol Dis. 2006 Aug;23(2):260-72. PubMed.
  5. . A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature. 2000 Dec 21-28;408(6815):979-82. PubMed.

External Citations

  1. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto
  2. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto

Further Reading

No Available Further Reading