Posted 26 July 2005

General Information

Transgene: Crossed APPV717I (London) with PS1A246E PS1A246E to produce bigenic mice.

Mutation: APP-V717I (London), PS1-A246E

Promoter: Mouse Thy1

Mouse strain: FVB/N

Phenotype

Neuropathological Analysis:

Bigenic mice co-express both transgenes in neurons only. Amyloidogeneic processing of APP metabolism was increased in the brain of the bigenic mice. At 6-9 months there were increased Aβ levels, concomittant with earlier and increased amyloid plaques and vascular amyloid (CAA) compared to the single APP/London tg mice, which develop plaques and CAA at 12-15 months.

Mutant PS1 aggravated parenchymal and cerebrovascular amyloid pathology (Van Dorpe, 2000) by increasing Aβ42 production, as opposed to aging in single APP-V717I mice in which the increased amyloid pathology did not result from increased Aβ42 production, but from a decreased clearance (Dewachter et al, 2000). Increased Ca2+ release from the ER in mutant PS1 neurons was dependent on the presence of APP and its processing by PS1 (i.e. amyloidβ and APP C99 fragments) (Herms et al, 2003).

Behavioral

normal

Availability

Mice can be made available for academic collaboration under MTA with KULeuven-R&D. For information on these mice, please contact:

Paul Van Dun
Director - KULeuvenR&D
Groot Begijnhof 59
B-3000 Leuven Belgium
tel +32 16 326508
fax +32 16 326515
Email: Paul.Vandun@lrd.kuleuven.ac.be
Web site: http://www.kuleuven.ac.be/lrd

References

Primary:

Dewachter I. 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. 2000 Sep 1;20(17):6452-8. Abstract

Associated:

Dewachter I, Reversé D, Caluwaerts N, Ris L, Kuipéri C, Van den Haute C, Spittaels K, Umans L, Serneels L, Thiry E, Moechars D, Mercken M, Godaux E, Van Leuven F. Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice. J Neurosci. 2002 May 1 ; 22(9):3445-53. Abstract

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 Angioplathy in APP/London transgenic mice. Am J Pathol (2000) 157:1283-1298. Abstract

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. Abstract

Herms J, Schneider I, Dewachter I, Caluwaerts N, Kretzschmar H, Van Leuven F. Capacitive calcium entry is directly attenuated by mutant presenilin-1, independent of the expression of the amyloid precursor protein. J Biol Chem. (2003) 278: 2484-2489. Abstract

Moechars D. 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. Abstract .