Updated 24 May 2010
Transgene: Human APP695 cDNA harboring the Swedish double mutation (KM670/671NL)
was subcloned into exon 3 of the Thy1.2 expression cassette. Human four-repeat tau
without amino terminal inserts (4R0N) harboring the hP30lL mutation was also subcloned
into Thy1.2 expression cassette. The two were comicroinjected into the pronuclei
of single-cell embryos harvested from homozygous PS1M146V knockin mice
Mutation: APP Swedish (KM670/671NL), Tau P301L and PS1 M146V mutations
Promoter: Thy-1.2 promoter
Mouse strain: B6;129-Psen1tm1Mpm
Tg(APPSwe,tauP301L)1Lfa/J. The PS1 knockin mice were originally generated as a hybrid
129/C57BL6 background. Founder mice were backcrossed to the parental PS1 knockin
mice. Both hemizygous and homozygous 3×Tg-AD mice were propagated. Mice are also
being established on a pure FVB/N background and on a pure C57/BL6 background. These
mice are currently at the n = 6 generation, and breeding will continue to the 10th
Trigenic-AD mice develop an age-related and progressive phenotype including plaques
and tangles. Synaptic dysfunction, including LTP deficits, manifests in an age-related
manner, but before plaque and tangle pathology. Deficits in long-term synaptic plasticity
correlate with the accumulation of intraneuronal Aβ. Tau and APP expression
are doubled in the homozygous mice. Hippocampus and cerebral cortex contained highest
steady-state levels of hAPP and Tau proteins. Cerebellum did not contain any transgenic
proteins. Extracellular Aβ deposits first apparent in 6-month-old mice in the
frontal cortex, and were readily evident by 12 months. No tau alterations are apparent
at 6 months. There is a progressive increase in Aβ formation as a function
of age in the trigenic-AD brains and a particularly pronounced effect on Aβ42
The mice develop cognitive impairments by 4 months of age. The first impairments
manifest as a retention/retrieval deficit and not as a learning deficit, and occur
prior to the occurrence of any plaque or tangle pathology. The mice show deficits
on both spatial and contextual based paradigms. This early cognitive deficits can
be reversed by immunotherapy.
The Jackson Lab
, available, Stock #004807. Use of mice only available to non-profit entities.
Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson
MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer's disease with plaques
and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21.
Yao PJ, Bushlin I, Furukawa K. Preserved synaptic vesicle recycling in hippocampal
neurons in a mouse Alzheimer’s disease model. Biochem. Biophys. Res. Comm. 330(1):
34-38, 2005. Abstract.
Billings, L., Oddo, S., Green, K. N., McGaugh, J. L., and LaFerla, F. M. (2005).
Intraneuronal Aβ causes the onset of early Alzheimer's disease-related cognitive
deficits in transgenic mice. Neuron 45, 675-688.
Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H., and LaFerla, F. M. (2004).
Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated
tau aggregates via the proteasome. Neuron 43, 321-332.
Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM. Amyloid deposition precedes
tangle formation in a triple transgenic model of Alzheimer's disease. Neurobiol
Aging 24(8):1063-70, 2003.