Updated 25 January 2006

General Information

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 PS1_M146V knockin mice (Guo).

Mutation: APP Swedish (KM670/671NL), Tau P301L and PS1 M146Vmutations

Promoter: Thy-1.2 promoter

Mouse strain: 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 generation.

Phenotype

Neuropathological analysis

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 levels.

Behavioral

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.

Availability

Frank M. LaFerla
Department of Neurobiology and Behavior
University of California Irvine
Irvine, CA 92697 USA
(949) 824-1232
(949) 824-7356
Email: laferla@uci.edu

Patents: None

References

Primary:

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. Abstract

Associated:

Oddo S, Caccamo A, Tran L, Lambert MP, Glabe CG, Klein WL, Laferla FM. Temporal Profile of Amyloid-beta (Abeta) Oligomerization in an in Vivo Model of Alzheimer Disease: A Link Between Abeta And Tau Pathology. J Biol Chem. 2006 Jan 20;281(3):1599-604. Epub 2005 Nov 10. Abstract

Janelsins MC, Mastrangelo MA, Oddo S, LaFerla FM, Federoff HJ, Bowers WJ. Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer's disease mice. J Neuroinflammation. 2005 Oct 18;2:23. Abstract

Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. J Neurosci. 2005 Sep 28;25(39):8843-53. Abstract

Smith IF, Hitt B, Green KN, Oddo S, LaFerla FM. Enhanced caffeine-induced Ca2+ release in the 3xTg-AD mouse model of Alzheimer's disease. J Neurochem. 2005 Sep;94(6):1711-8. Abstract

Oddo S, Caccamo A, Green KN, Liang K, Tran L, Chen Y, Leslie FM, LaFerla FM. Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):3046-51. Abstract

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. Abstract

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. Abstract

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. Abstract