reMYND’s APP-London model

The APP[V717I] (APP-London, APP-Ld) mouse model recapitulates important pathological and clinical hallmarks of Alzheimer’s disease [1, 2, 3] and has proven a valuable paradigm for evaluating Abeta directed approaches in general and a preferred model for testing anti beta-secretase and anti gamma-secretase inhibitor/modulator approaches in particular.

Historically, both the parenchymal and vascular amyloid deposits, and more recently, truncated and pyroglutamate-modified Abeta3(pE)-42 species, are perceived as important hallmarks of AD-pathology. Late stage symptoms are preceded by robust deficits in orientation and memory that correlate in time with Abeta oligomerization and GSK3beta-mediated phosphorylation of endogenous murine Tau, all markers that have gained considerable interest during the last decade. The table below summarizes the key characteristics of reMYND’s proprietary APP[V717I] Alzheimer transgenic mice.

reMYND's APP-London model
Summary

Model

Key Characteristics

APP[V717I] -

London mutation

  • Expression of hAPP under control of moThy-1 gene promoter
  • More gentle AD phenotype
    • Later-age amyloid plaque development (hippocampus, subiculum and cortex; as of 10.5 months
    • Cognitive impairment; deficit in spatial reference memory (MWM) testing
    • Early Aβ-induced GSK3-activation and TAU phos phorylation in hippocampus
    • CAA pathology (as of 15-18 months)
    • Dystrophic neurites containing hyperphosphorylated moTau (no tangle-pathology)
    • Micro-bleedings (as of 25-30 months)
Moechars et al., JBC 1999.
Van Dorpe et al., AJP, 2000.
Terwel et al., AJP, 2008

Complementary to the late onset APP-Ld single transgenics, an APP[V717I]xPS1[A246E] bigenic model has been developed being a more aggressive model with accelerated amyloid pathology.

A review paper, entitled ‘Pathological hallmarks, clinical parallels and value for drug testing in Alzheimer's disease of the APP[V717I] London transgenic mouse model’ reviews all key early and late hallmarks of the Alzheimer pathology in this model, and discusses clinical parallels with AD patients and the value of the APP-London transgenic mouse model for preclinical in vivo testing of experimental Alzheimer therapies. The paper also touches on reMYND’s other proprietary mouse models and is freely downloadable here.

For more information and all inquiries, please contact Bart Roucourt, CRO Manager.

References:
[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. 274(10):6483-92 (1999). 

[2] Van Dorpe J, Smeijers I, 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. x 157:1283-98 (2000).
[3] Terwel D, Muyllaert D, Dewachter I, Borghgraef P, Croes S, Devijver H, Van Leuven F. Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice. Am J Pathol. 172(3):786-98 (2008).