Updated 28 January 2005

General Information

Transgene: PS1cDNA (VRSQ-)

Mutation: M146L

Targeted region (if applicable): n/a

Promoter: Rat PDGF-β (1.4 kb Xba fragment)

Coding region: 1.4kb PS1 from ATG start to TGA stop site

Intron: 3kb PS1 intron 5 inserted at endogenous locus in cDNA PolyA tail for SV40

Mouse Strain: Swiss Webster Tac) x B6D2F1 (Tac)

Phenotype

Null mutant phenotype: n/a

Lethality/viability/fecundity: normal for all parameters. Above average fecundity.

Homozygous/heterozygous viability: both are viable

Relative Protein expression level to endogenous:
Beta Amyloid: n/a
Presenilin: 2-3 folds (by quantitative western)
Tau: n/a

Neuropathological Analysis:

No abnormal pathology up to 2.5 years. High level of PS1 expression and elevated Aβ (Duff, 1996); altered mitochondria activity (Bengley, 1999), disregulation of calcium homoeostasis (Bengley, 1999; Barrow, 2000).

APP/PS1 develop impairment of special memory, with reduced glucose utilization and a 35.8% dropout of neurons in the CA1 region (Sadowski, 2004). Widespread Aβ plaques found in white and gray matter. (Kurt, 2001). Hyperphosphorylated tau appears after the onset of Aβ depositition (Kurt, 2003).

Behavioral:

No abnormal behavior in Morris water maze (Duff, 1996) Electrophysiological assessment: altered AHP in mutants (Barrow, 2000).

Licensing/academic distribution contact information:

Wendy Davies,
University of South Florida
WDAVIS@RESEARCH.USF.EDU

Patents:

Reference

Primary:

Duff, K., Eckman, C., Zehr, C., Yu, X., Prada, C.M., Perez-tur, J., Hutton, M., Buee, L., Harigaya, Y., Yager, D., Morgan, D., Gordon, M.N., Holcomb, L., Refolo, L., Zenk, B., Hardy, J. and Younkin, S. (1996) Increased Aβ42(43) in brains of mice expressing mutant presenilin 1. Nature 383 710-713. Abstract.

Associated:

Barrow PA, Empson RM, Gladwell SJ, Anderson CM, Killick R, Yu X, Jefferys JG, Duff K. Functional phenotype in transgenic mice expressing mutant human presenilin-1. Neurobiol Dis. 2000 Apr ; 7(2):119-26. Abstract.

Begley JG, Duan W, Chan S, Duff K, Mattson MP. Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice. J Neurochem. 1999 Mar ; 72(3):1030-9. Abstract .

Related:

Roach JT, Volmar CH, Dwivedi S, Town T, Crescentini R, Crawford F, Tan J, Mullan M. Behavioral effects of CD40-CD40L pathway disruption in aged PSAPP mice. Brain Res. 2004 Jul 23;1015(1-2):161-8. Abstract

Trinchese F, Liu S, Battaglia F, Walter S, Mathews PM, Arancio O. Progressive age-related development of Alzheimer-like pathology in APP/PS1 mice. Ann Neurol. 2004 Jun 1 ; 55(6):801-14. Abstract.

Sadowski M, Pankiewicz J, Scholtzova H, Ji Y, Quartermain D, Jensen CH, Duff K, Nixon RA, Gruen RJ, Wisniewski T. Amyloid-beta deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice. J Neuropathol Exp Neurol. 2004 May;63(5):418-28. Abstract

Kurt MA, Davies DC, Kidd M, Duff K, Howlett DR. Hyperphosphorylated tau and paired helical filament-like structures in the brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1 transgenes. Neurobiol Dis. 2003 Oct;14(1):89-97. Abstract.

Kurt MA, Davies DC, Kidd M, Duff K, Rolph SC, Jennings KH, Howlett DR. Neurodegenerative changes associated with beta-amyloid deposition in the brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1 transgenes. Exp Neurol. 2001 Sep;171(1):59-71. Abstract.

Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K, Pappolla MA. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000 Aug 1 ; 7(4):321-31. Abstract.

Takeuchi A, Irizarry MC, Duff K, Saido TC, Hsiao Ashe K, Hasegawa M, Mann DM, Hyman BT, Iwatsubo T. Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss. Am J Pathol. 2000 Jul ; 157(1):331-9. Abstract.

Holcomb LA, Gordon MN, Jantzen P, Hsiao K, Duff K, Morgan D. Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid deposits. Behav Genet. 1999 May ; 29(3):177-85. Abstract.

Wong TP, Debeir T, Duff K, Cuello AC. Reorganization of cholinergic terminals in the cerebral cortex and hippocampus in transgenic mice carrying mutated presenilin-1 and amyloid precursor protein transgenes. J Neurosci. 1999 Apr 1 ; 19(7):2706-16. Abstract.

Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, Wright K, Saad I, Mueller R, Morgan D, Sanders S, Zehr C, O'Campo K, Hardy J, Prada CM, Eckman C, Younkin S, Hsiao K, Duff K. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med. 1998 Jan 1 ; 4(1):97-100. Abstract.