Updated 30 October 2005

General Information

Transgene: human APP695 cDNA; expresson cassette retains ~90 nucleotides of the APP mRNA 5'-untranslated region adjacent to the start codon

Mutation: APP695 with double mutations at KM670/671/NL (Swedish mutation), along with V717F (Indiana mutation)

Promoter: Syrian hamster prion promoter

Mouse Strain: Hybrid C3H/He-C57BL/6

Phenotype

Neuropathological Analysis:

Thioflavine S-positive Aβ amyloid deposits present at 3 months of age; dense cored plaques and neuritic pathology by 5 months. Glia surrounding deposits, suggesting inflammatory response. Activated microglia appear concurrently with plaques.

3,200 - 4,600 pmol Aβ42 per gram brain at 6 months, with more Aβ42 than Aβ40.

Behavior and age of phenotype:

• Low survival rates, 50% death by 3 months (Chishti et al., 2001)
• WM spatial memory retention, acquisition, 11 weeks (Chishti et al., 2001)
• Auditory startle, (progressive) 6-7, 10-12, 12-14, 15-17 weeks (McCool et al., 2003)
• Paired pulse inhibition, 6-8, 12-14, 15-17 weeks (McCool et al., 2003)

Variations and Experiments:

In TgCRND8 mice also expressing two presenilin-1 transgenes with familial AD mutations (M146L and L286V), deposition of amyloid was accelerated, appearing as early as 1 month of age.

With Aβ peptide immunization, plaque burden and behavioral impairment are ameliorated, though not to wild-type levels.

Studied survival of mice (365 days) on different genetic backgrounds:
(C57) × (C3H/C57) 50% survived
(C3H/C57/129SvEv/Tac) × (129SvEv/Tac) 25% survived
(FVB)×(C3H/C57) 17% survived.

Availability

Contact David Westaway

Patents: None

References

Primary Reference

Chishti MA, Yang D-S, Janus C, Phinney AL, Horne P, Pearson J, Strome R, Zuker N, Loukides J, French J, Turner S, Lozza G, Grilli M, Kunicki S, Morissette C, Paquette J, Gervais F, Bergeron C, Fraser PE, Carlson GA, St. George-Hyslop P, Westaway D. Early-onset amyloid deposition and cognitive deficits in tansgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem. 15 Jun 2001;276(24):21562-70. Abstract.

Associated References

Janus C, Welzl H, Hanna A, Lovasic L, Lane N, St George-Hyslop P, Westaway D. Impaired conditioned taste aversion learning in APP transgenic mice. Neurobiol Aging. 2004 Oct;25(9):1213-9. Abstract

Del Vecchio RA, Gold LH, Novick SJ, Wong G, Hyde LA. Increased seizure threshold and severity in young transgenic CRND8 mice. Neurosci Lett. 2004 Sep 2;367(2):164-7. Abstract

Touma C, Ambree O, Gortz N, Keyvani K, Lewejohann L, Palme R, Paulus W, Schwarze-Eicker K, Sachser N. Age- and sex-dependent development of adrenocortical hyperactivity in a transgenic mouse model of Alzheimer's disease. Neurobiol Aging. 2004 Aug;25(7):893-904. Abstract

Dudal S, Krzywkowski P, Paquette J, Morissette C, Lacombe D, Tremblay P, Gervais F. Inflammation occurs early during the Abeta deposition process in TgCRND8 mice. Neurobiol Aging. 2004 Aug ; 25(7):861-71. Abstract

Suo Z, Wu M, Citron BA, Wong GT, Festoff BW. Abnormality of G-protein-coupled receptor kinases at prodromal and early stages of Alzheimer's disease: an association with early beta-amyloid accumulation. J Neurosci. 2004 Mar 31;24(13):3444-52. Abstract.

McCool MF, Varty GB, Del Vecchio RA, Kazdoba TM, Parker EM, Hunter JC, Hyde LA.Increased auditory startle response and reduced prepulse inhibition of startle in transgenic mice expressing a double mutant form of amyloid precursor protein. Brain Res. 2003 Dec 19;994(1):99-106. Abstract.

Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HTJ, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D. Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature. 21/28 Dec 2000;408:979-81. Abstract.