reMYND’s APP-London model and its bigenic combination with PS1[A246E]
reMYND’s proprietary APP[V717I] transgenic, modeling a progressive amyloid-o-pathy and therefore serving as an excellent model for Alzheimer’s disease (AD), is also available in combination with PS1[A246E], the bigenic model showing the same pathological hallmarks but with a different timing of onset and severity.
The APP[V717I] (APP-London, APP-Ld) mouse model recapitulates important pathological and clinical hallmarks of Alzheimer’s disease [1, 2, 3] and is therefore a valuable paradigm for evaluating therapeutic candidates. Historically, both the parenchymal (Figure 1A) 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 (Figure 1B) and GSK3beta-mediated phosphorylation of endogenous murine Tau, all markers that have gained considerable interest during the last decade.
Complementary to the late onset APP-Ld single transgenics, an APP[V717I]xPS1[A246E] bigenic model has been developed being a more aggressive model (Figure 1C) with accelerated amyloid pathology [4]. These mice carry additionally the human PS1[A246E] transgene, also under control of the murine thy1 gene promoter, containing a clinical mutation in the transmembrane region.
Figure 1. Abeta aggregation prior to plaque formation in APP[V717I] (APP-Ld) and APP[V717I]xPS1[A246E] mice. (A) Representative photo collection of anti-Abeta stained sections showing total plaque load in APP-Ld mice of different ages (proprietary anti-Abeta Nanobody®, reMYND/Ablynx, Belgium). (B) Aggregated Abeta in APP-Ld mice of different ages, both in pre-plaque (indicated by the dashed line) and post-plaque stages of the Alzheimer pathology (A4-assay, Amorfix Life Sciences Ltd., Mississauga, Canada). (C) As in B, for the APP[V717I]xPS1[A246E] model. The signal of non-transgenic mice was under the S/N cut-off value (data not shown).
The table below summarizes the key characteristics of reMYND’s proprietary APP[V717I] and APP[V717I]xPS1[A246E] Alzheimer transgenic mice, recapitulating important pathological and clinical hallmarks of Alzheimer’s disease and therefore valuable paradigms for evaluating therapeutic candidates.
A non-confidential data package on reMYND’s APP[V717I] and hAPP[V717I]xPS1[A246E] model can be downloaded here.
A recent 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, please contact Dr. An Tanghe .
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). [4] Dewachter I, Van Dorpe J, Smeijers L, Gilis M, Kuipéri C, Laenen I, Caluwaerts N, Moechars D, Checler F, Vanderstichele H, Van Leuven F. Aging increased amyloid peptide and caused amyloid plaques in brain of old APP/V717I transgenic mice by a different mechanism than mutant presenilin1. J. Neurosci. 20:6452-58 (2000).
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