B6.Cg-Tg(APP695)3Dbo Tg(PSEN1dE9)S9Dbo/Mmjax

Stock number: 005866
Product name: APPswe/PS1dE9
Strain synonyms: APPswe line C3-3 x PS1dE9 line S-9
Research areas: Mouse/Human Gene Homologs, Neurobiology Research

Description

These double-transgenic mice show increased amyloid plaque deposition with age along with deficits in cognitive tasks and episodic-like memory tasks.

Detailed description

Double transgenic mice are viable and fertile. At 6 months of age, double-transgenic mice show visible amyloid plaque deposition but are indistinguishable from nontransgenic animals in all cognitive measures. By 18 months, amyloid deposits were much higher in APPswe/PS1dE9 mice with statistically significant but mild decreases in cholinergic markers (cortex and hippocampus) and somatostatin levels (cortex). Performance of older double-transgenic mice is impaired in all cognitive tasks, and deficits in episodic-like memory tasks correlate with total amyloid-beta peptide loads in the brain. Mutant mice, hemizygous for each transgene, and on the C57BL/6J background (N6), have altered EEG (decreased cortical theta activity and increased beta and gamma activity). EEG differences are detected as early as 7 month of age (Wang et al. Brain Res 2002).

Development

Mutant amyloid precursor protein (APPswe) transgenic mice (line C3-3) express a chimeric mouse/human APP-695 with mutations linked to familial Alzheimer's disease (KM 593/594 NL; also called K670N/M671L). The C3-3 line was backcrossed to C57BL/6J mice for 10 generations. Presenilin 1 (PSEN1) transgenic mice (line S-9) express human PSEN1 carrying the exon-9-deleted variant (PSEN1dE9) associated with familial Alzheimer's disease. Originally created on a hybrid strain background (C3H/HeJ;C57BL/6J), the S-9 line was backcrossed to C57BL/6J for six generations. Both are under the control of the mouse prion protein (PrP) promoter, directing transgene expression predominantly to CNS neurons. APPswe/PS1dE9 double transgenic mice were produced by mating APP-695 line C3-3 males to PS1dE9 line S-9 females, and then backcrossing double transgenic males to C57BL/6J mice for 10 generations before arriving at the MMRRC at The Jackson Laboratory.

Allele

Symbol: Tg(APP695)3Dbo
Name: transgene insertion 3, David R Borchelt
MGI accession ID: MGI:2447334
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Marker symbol: Tg(APP695)3Dbo
Marker name: transgene insertion 3, David R Borchelt
Chromosome: UN
Strain of origin: (C57BL/6J x C3H/HeJ)F2
Expressed genes: APP695,amyloid beta (A4) precursor protein (chimeric),mouse/human chimera
Molecular note: The transgene is composed of a cDNA encoding a chimeric APP protein regulated by the mouse prion promoter. The chimeric APP molecule was created by replacing sequences encoding the Abeta domain of a 695 amino acid isoform of the murine sequence with the cognate sequences of the human gene (mutations K595N, M596L). The human mutations are found in familial Alzheimer's disease. Transgene expression was observed in the brain and heart by Western blot analysis using a monoclonal antibody recognizing the human Abeta region.
General note: Three transgenic lines were generated and designated by the authors lines Q2-2, E1-2 (Tg(Prnp-App/APPswe)E1-2Dbo) and C3-3.

This line was generated from founder number C3-3.

Transgenic mice develop amyloid deposits in brain tissue by 18-20 months of age.

Transgenic mice that are also transgenic for Tg(PSEN1)5Dbo express both human presenilin 1 (A246E variant) and a chimeric amyloid precursor protein (APPSwe) under direction of the mouse prion protein promoter. Elevated levels of the AB1-42(43) peptide are detected in brain homogenates. By nine months of age, histological examination of brain tissue from these mice reveals numerous amyloid deposits resembling those observed in the brains of patients with Alzheimer's disease (AD). The number of amyloid deposits increases dramatically between the ages of 10 and 12 months.

Allele

Symbol: Tg(PSEN1dE9)S9Dbo
Name: transgene insertion S9, David R Borchelt
MGI accession ID: MGI:3618599
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Marker symbol: Tg(PSEN1dE9)S9Dbo
Marker name: transgene insertion S9, David R Borchelt
Chromosome: UN
Strain of origin: (C57BL/6J x C3H/HeJ)F2
Expressed genes: PSEN1,presenilin 1,human
Molecular note: The coding sequence of the transgene is derived from the cDNA of the familial Alzheimer disease- (FAD-) associated deltaE9 variant of human presenilin 1, which has a splice acceptor mutation upstream of exon 9 that results in a protein lacking amino acids 290-319. The mutant cDNA replaces the coding region of the mouse prion protein (Prp) gene in a construct that contains ~6 kb of genomic DNA upstream of the primary PRP translation start site and includes the noncoding first exon and first intron and, following the inserted PSEN1 sequence, ~3 kb of 3' untranslated sequence; this construct has been shown to drive expression in both neurons and glial cells of the central nervous system (CNS).
General note:

The deltaE9 PSEN1 protein variant fails to undergo endoproteolysis in cultured lymphoblasts from an affected human carrier and instead accumulates as the full-length, 40 kDa mutant protein (J:34323). Similarly, immunoblotting of of cortical and hippocampal extracts from transgenic mice under conditions that distinguish mouse and human full-length PSEN1 and their endoproteolytic derivatives demonstrates failure of the transgenic protein to undergo endoproteolysis. (J:104147)

The amount of full-length mutant human PSEN1 in brains of deltaE9 PSEN1 transgenic mice exceeds by ~60% the cumulative amount of the full-length human PSEN1 and its N-terminal derivative in brains of transgenic mice expressing wild-type human PSEN1. (J:104147)