Genes: APP, MAPT, PSEN2
Mutations: APP KM670/671NL (Swedish), MAPT P301L, PSEN2 N141I (Volga German)
Modification: APP: Transgenic; MAPT: Transgenic; PSEN2: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6.D2-Tg(Thy1-APPSwe, Prp-PSEN2N141I, Thy1-TauP301L)
Genetic Background: C57BL/6, DBA/2; backcrossed to C57BL/6
Availability: Available through Laurence Ozmen.
These triple transgenic mice express mutant APP, PSEN2, and MAPT. They show age-dependent accumulation of Aβ plaques and neurofibrillary tangle-like pathology, starting around four months of age (Grueninger et al., 2010).
Phosphorylated tau accumulates in the subiculum and the CA1 region of the hippocampus at four months. Neurofibrillary tangles also appear in these regions as well as the amygdala. Dystrophic neurites have also been observed along with neuropil threads containing abnormally phosphorylated tau. No overt neuronal loss. Amyloid plaques (Grueninger et al., 2010).
Impaired spatial learning in the Morris water maze at four months, but impairment is not progressive between four and twelve months and appears to be independent of pathology (Grueninger et al., 2010).
Cortex-specific deficiencies in oxidative phosphorylation. Loss of mitochondrial membrane potential. Reduced cortical ATP. Increased superoxide anions and reactive oxygen species compared to wild-type controls (Rhein et al., 2009). No differences in APP expression, APP cleavage or Aβ accumulation compared to the double transgenic mouse PS2APP. Levels of tau phosphorylated at serine 422 increased in an age-dependent manner, but levels of tau phosphorylated at threonine 231 did not (Grueninger et al., 2010).
These animals were generated by crossing homozygous PS2APP mice (line B6.152H) to hemizygous tau mice (line B6.TauP301L). PS2APP were generated by co-injecting two transgenic constructs: human PSEN2 (N141I mutation) and human APP (Swedish mutation) driven by the mouse prion promoter and the mouse Thy1 promoter respectively (Ozmen et al., 2009). The transgenic TauP301L mouse (line pR5) expresses the human tau40 isoform driven by the Thy1.2 promoter (Kins et al., 2001).
Available through Laurence Ozmen.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Synaptic Loss
- Changes in LTP/LTD
Rare amyloid plaques at 4 months, plaques become more abundant with age. By 8 months the number of amyloid plaques increases considerably in the subiculum and the CA1 region of the hippocampus (Grueninger et al., 2010).
Abnormally phosphorylated tau is detectable at 4 months in both TauPS2APP and tau single transgenic mice especially in the subiculum, amygdala, and the CA1 region of the hippocampus. Tau pathology increases with age with numerous tangle-like deposits in the hippocampus confirmed by Gallyas silver staining at 16 months (Grueninger et al., 2010).
No overt neuronal loss in the hippocampus at 16 months (Grueninger et al., 2010).
Changes in LTP/LTD
Impairment is not age-associated and does not progress from age 4 months to 12 months (Grueninger et al., 2010).
Research Models Citations
- Grueninger F, Bohrmann B, Czech C, Ballard TM, Frey JR, Weidensteiner C, von Kienlin M, Ozmen L. Phosphorylation of Tau at S422 is enhanced by Abeta in TauPS2APP triple transgenic mice. Neurobiol Dis. 2010 Feb;37(2):294-306. PubMed.
- Rhein V, Song X, Wiesner A, Ittner LM, Baysang G, Meier F, Ozmen L, Bluethmann H, Dröse S, Brandt U, Savaskan E, Czech C, Götz J, Eckert A. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20057-62. PubMed.
- Ozmen L, Albientz A, Czech C, Jacobsen H. Expression of transgenic APP mRNA is the key determinant for beta-amyloid deposition in PS2APP transgenic mice. Neurodegener Dis. 2009;6(1-2):29-36. PubMed.
- Kins S, Crameri A, Evans DR, Hemmings BA, Nitsch RM, Gotz J. Reduced protein phosphatase 2A activity induces hyperphosphorylation and altered compartmentalization of tau in transgenic mice. J Biol Chem. 2001 Oct 12;276(41):38193-200. Epub 2001 Jul 25 PubMed.
- Loreth D, Ozmen L, Revel FG, Knoflach F, Wetzel P, Frotscher M, Metzger F, Kretz O. Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathy. Neurobiol Dis. 2012 Jul;47(1):1-12. PubMed.
- Collin L, Bohrmann B, Göpfert U, Oroszlan-Szovik K, Ozmen L, Grüninger F. Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer's disease. Brain. 2014 Oct;137(Pt 10):2834-46. Epub 2014 Jul 31 PubMed.