Updated 27 May 2005

General Information

Transgene: APP695 human cDNA

Mutation: human APP_V717I known as the "London" mutation (J. Hardy)

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 but no introns are present in the APP cDNA

Targeted region: brain, neurons

Mouse strain: FVB/N, C57Bl/6

Phenotype

Null mutant phenotype: NA

Lethality/viability/fecundity: Normal fertility of heterozygous males and females. In open animal house premature death is evident mainly due to stress (male aggression). In SPF conditions and with males housed singly, premature death is low.

Homozygous/heterozygous viability: Strain is maintained "heterozygous" only, transgenic females in 2 genetic backgrounds (FVB and C57Bl/6) [Note: eventually C57Bl6 females are used to generate F1 offspring for water maze, behavior tests - cfr Moechars et al, 1999]

Relative Protein expression level to endogenous
Beta Amyloid: APP[V717I] ~ 3 fold higher than endogenous murine APP;
Aβ40 ~ 4 ng/g and Aβ42 ~1 ng/g wet brain weight
Presenilin: NA
Tau: NA

Neuropathological analysis

H/E : normal up to 2 yrs of age
ThioflavinS and silver: amyloid plaques and cerebrovascular angiopathy - onset 10-12 months

Immunohistochemical: amyloid neuritic plaques after 10-12 months, positive with various APP and Ab antibodies, with thioflavinS, Garvey silver-staining. Plaques are immunopositive for many different associated proteins, i.e. ubiquitin , synaptophysin , Cathepsin D, ?

Plaque-associated dystrophic neurites contain hyper-phosphorylated tau (AT8, AT100 positive).

Reactive astrocytes and microglia surround the plaques.

Prominent cerebral amyloid angiopathy (CAA) is present after 12-15 months, with vascular amyloid preferentially deposited in arterioles, ranging from small focal to large circumferential depositions. Ultrastructural: disrupted external elastic lamina, thinning of the internal elastic lamina, interruption of the smooth muscle layer, and loss of smooth muscle cells (Van Dorpe et al, 2000).

Prominent cerebral amyloid angiopathy is present after 12-15 months.

Vascular amyloid is preferentially deposited in arterioles, ranging from small focal to large circumferential depositions; ultrastructural: disrupted external elastic lamina, thinning of the internal elastic lamina, interruption of the smooth muscle layer, and loss of smooth muscle cells.

Structural: cholinergic fiber distortion and de-afferentiation around amyloid plaques in subiculum in brain of old APP/London mice (> 15 months)

Behavioral

Morris Water Maze:

increased escape latency in the place navigation test,

decreased dwell-time in correct quadrant in probe test

normal escape latency in cue-navigation test

normal swim-speed

Other:

decreased exploration

increased neophobicity

increased male aggressivity (resident-intruder test)

increased sensitivity to kainic acid

decreased sensitivity to NMDA

decreased glutamate re-uptake, and decreased protein EAAT1 and EAAT2

Electrophysiological assessment

decreased long term potentiation (LTP), partially restored by neuron specific deletion of PS 1 (Dewachter et al, 2002)

normal paired pulse facilitation

Therapeutic agent studies performed

risperidone (Risperdal, J&J) - Moechars et al, 1998

"beta-sheet breakers (Parmanne et al, 2002)
vaccination with bacteriophage (Frenkel et al, 2003)

Crosses to create multigenic mouse

crosses with PS1 (wt and A246E), with Tau4R, and [P301L], with ApoE4, ADAM10, BACE1

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

Reference

Primary:

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. Abstract .

Associated:

Vanhoutte G. Noninvasive in vivo MRI detection of neuritic plaques associated with iron in APP[V717I] transgenic mice, a model for Alzheimer's disease. Magn Reson Med. 2005 Mar 1;53(3):607-13. Abstract.

Van Dooren T, Dewachter I, Borghgraef P, van Leuven F. Transgenic mouse models for APP processing and Alzheimer's disease: early and late defects. Subcell Biochem, 38:45-63, 2005 (review). Abstract.

Willem M, Dewachter I, Smyth N, Van Dooren T, Borghgraef P, Haass C, Van Leuven F. beta-site amyloid precursor protein cleaving enzyme 1 increases amyloid deposition in brain parenchyma but reduces cerebrovascular amyloid angiopathy in aging BACE x APP[V717I] double-transgenic mice. Am J Pathol. 2004 Nov 1 ; 165(5):1621-31. Abstract.

Etcheberrigaray R, Tan M, Dewachter I , Kuipéri C, Van der Auwera I , Wera S, Qiao L, Bank B, Nelson TJ, Kozikowski AP, Van Leuven F and Alkon DL Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice. Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):11141-6. Abstract

Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, Flamez P, Dequenne A, Godaux E, Van Leuven F, Fahrenholz F. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest. 2004 May 1 ; 113(10):1456-64. Abstract

Frenkel D, Dewachter I, Van Leuven F, Solomon B. Reduction of β-amyloid plaques in brain of transgenic mouse models of Alzheimer's disease by EFRH-phage immunization. Vaccine (2003) 21:1060-1065. Abstract.

Permanne B, Adessi C, Saborio G P, Fraga S, Frossard M J, Van Dorpe J, Dewachter I, Banks W A, Van Leuven F, Soto C. Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer's disease by treatment with a β-sheet breaker peptide. FASEB J (2002) 16:860-862. 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 (2002) 157:1283-1298. Abstract.

Dewachter I, Reverse D, Caluwaerts N, Ris L, Kuiperi 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 [V7171] transgenic mice. J Neurosci (2002) 22:3445-3453. Abstract.

Masliah E, Alford M, Mallory M, Rockenstein E, Moechars D, Van Leuven F (2000) Abnormal glutamate transport function in mutant amyloid precursor protein transgenic mice. Exp Neurol (2000) 163 : 381-387. 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 levels 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.

Bronfman FC, Moechars D, Van Leuven F (2000) Acetylcholinesterase-positive fiber deafferentation and cell shrinkage in the septohippocampal pathway of aged APP/london transgenic mice. Neurobiol Disease (2000) 7: 152-168. Abstract.

Moechars D, Filis M, Kuiperi C, Laenen I, Van Leuven F. (1998) Aggressive behavior in transgenic mice expressing APP is alleviated by serotonergic drugs. Neuroreport 9:3561-3564. Abstract.