Species: Mouse
Genes: APP
Mutations: APP V717I (London)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Strain Name: Tg(Thy1-APPLon)2Vln/0
Genetic Background: Originally generated on FVB/N background; available at reMYND as C57BL/6xFVB/N
Availability: Available through the KU Leuven Research and Development Office; the CRO reMYND offers research services with this line.

Modification Details

Transgene containing human APP (isoform 695) with the London mutation driven by the Thy1 promoter.

Neuropathology

Plaques start in the subiculum at ten months, spreading to the frontal cortex as dense and diffuse aggregates. Frequent deposits in the hippocampus and cortex, with occasional deposits in the thalamus and fimbria, external capsule, pontine nuclei, and white matter. Dystrophic neurites containing hyperphosphorylated tau, but no tangle pathology (Moechars et al., 1999). Prominent amyloid deposits in brain vessels after 15 months. Microbleeds at 25-30 months (Van Dorpe et al., 2000). Amyloid-associated inflammation. Decreased Aβ42/Aβ40 ratio at 15 months.

Cognition/Behavior

From the age of six months, spatial and non-spatial orientation and memory deficits by Morris water maze. Impaired associative learning. Increased agitation/anxiety from eight weeks. Reduced ambulation, especially with age. Hyperactivity and aggression.

Other Phenotypes

Increased mortality (72 percent by day 180). Increased incidence of seizures.

Note

These mice were reported in conjunction with another line (APP/Ld/6) that also expresses human APP with the London mutation driven by the Thy1 promoter. Transgene expression is higher in APP/Ld/2 mice than in APP/Ld/6 and the former have been more extensively characterized. In both lines APP protein is expressed in the hippocampus, parietal cortex, and frontal cortex at levels 2-5x higher than endogenous murine APP, with lower levels in the olfactory bulb and thalamus (Moechars et al., 1999).

This model has been used to test potential AD therapeutics (e.g. see Apr 2013 news story). APP models containing the London mutation may be particularly suitable for testing BACE inhibitors and modulators as the mutation is situated away from the β-cleavage site.

These mice have been used to generate bigenic animals, including APP(V717I) x PS1(A246E), which have elevated Aβ in the brain and develop plaques by six to nine months. This is earlier than the APP(V717I) single transgenics or the single transgenic PS1(A246E) mice which do not develop amyloid pathology (Schneider et al., 2001).

Availability

Available for non-commerical use through the KU Leuven Research and Development Office, contact Paul Van Dun or Olivier Lescroart. Research with this model is available at the contract research organization, reMYND (CRO@remynd.com).

Phenotype Characterization

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References

News Citations

1. First Stab at Combination Therapy Yields Additive Effect 8 Apr 2013

Research Models Citations

1. APP(V717I) x PS1(A246E)

Paper Citations

1. Moechars D, Dewachter I, Lorent K, Reversé D, Baekelandt V, Naidu A, Tesseur I, Spittaels K, Haute CV, Checler F, Godaux E, Cordell B, Van Leuven F. Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem. 1999 Mar 5;274(10):6483-92. PubMed.
2. Van Dorpe J, Smeijers L, Dewachter I, Nuyens D, Spittaels K, Van den Haute C, Mercken M, Moechars D, Laenen I, Kuiperi C, Bruynseels K, Tesseur I, Loos R, Vanderstichele H, Checler F, Sciot R, Van Leuven F. Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the london mutant of human APP in neurons. Am J Pathol. 2000 Oct;157(4):1283-98. PubMed.
3. Schneider I, Reverse D, Dewachter I, Ris L, Caluwaerts N, Kuiperi C, Gilis M, Geerts H, Kretzschmar H, Godaux E, Moechars D, Van Leuven F, Herms J. Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation. J Biol Chem. 2001 Apr 13;276(15):11539-44. PubMed.

Other Citations

1. Paul Van Dun

External Citations

1. reMYND

Further Reading