Updated 14 April 2003

General Information

Transgene:     1.4 kb PS1 human cDNA

Mutation:        PS1 A246E

Targeted region (if applicable):     brain, neurons

Promoter: mouse thy-1 gene, i.e. a 1.5 kb BanI-XhoI genomic fragment with exon 2 to exon 4 deleted and replaced by a synthetic oligonucleotide linker cassette. The thymus specific regulatory elements in intron 3 are thereby deleted, making the resulting promoter "post-natal and neuron-specific"

Intron: : * intron 1a, 1b and 2 of the mouse thy1 gene are retained in the mini-gene
            * no introns are present in PS1 cDNA

Mouse strain:     FVB/N

Phenotype

Null mutant phenotype:     n/a

Lethality/viability/fecundity:     normal for all parameters.

Homozygous/heterozygous viability:     normal

Relative Protein expression level to endogenous:
Beta Amyloid:     Ab42/40 ratio increased in double Tg mice APP x PS1
Presenilin:     endogenous PS1 is completely replaced by human mutant PS1
Tau:     NA

Neuropathological analysis:

Histological and Immunochemical: Normal up to 2 years of age
* Increased sensitivity for kainic acid (ip): more seizures and neuronal apoptosis
* Earlier and more amyloid plaques and angiopathy in double transgenic mice, i.e. cross APP[V717I] x PS1[A246] - onset at 6-9 months as opposed to 12-15 months in single APP/Ld mice

Structural: Normal up to 2 years of age

Behavioral:

Morris Water Maze: Normal

No other behavioral abnormalities

Electrophysiological assessment: Facilitated induction of LTP

Other: Altered calcium homeostasis, i.e. increased glutamate-induced intracellular calcium levels, increased sensitivity to kainic acid with increased neuronal damage (death)

Therapeutic agent studies performed: * ongoing (proprietary)

Crosses to create multigenic mouse: Cross with APP [V717I] and with Tau4R

Availability

Licensing/academic distribution contact information:

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

Patents: None

References

Primary:

Schneider I, D. Reverse, I. Dewachter, L. Ris, N. Caluwaerts, C. Kuiperi, M. Gilis, H. Geerts, D. Moechars, H. Kretzschmar, E. Godaux, F. Van Leuven, J. Herms. Mutant Presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation. Abstract.

Associated:

Dewachter I, van Dorpe J, Spittaels K, Tesseur I, Van Den Haute C, Moechars D, Van Leuven F. Modeling Alzheimer's disease in transgenic mice: effect of age and of presenilin1 on amyloid biochemistry and pathology in APP/London mice. Exp Gerontol 2000 Sep;35(6-7):831-41. Abstract.

Dewachter I, Van Dorpe J, Smeijers L, Gilis M, Kuiperi C, Laenen I, Caluwaerts N, Moechars D, Checler F, Vanderstichele H, Van Leuven F. (2000) Ageing 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) 20 : 6452-6458. 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.