General Information

Updated 5 March 2009

Transgene: Human APP695 containing the double mutation Lys670-> Asn, Met671->Leu, was inserted into B6;SJL F2 mice using a hamster prion protein cosmid vector. The resultant transgenic mice were bred to C57BL/6 mice. The colony was maintained by mating hemizygotes to B6SJL F1 mice. The model was transferred to Taconic from Mayo Foundation in March 1999.

Mutation: KM670/671NL

Promoter: hamster prion protein gene promoter

Mouse Strain: B6;SJL-Tg (APPSWE) 2576Kha

Phenotype

Neuropathological Analysis:

Transgenic mice 11-13 months of age show a 14-fold increase in Aß (1-42/43) over those at 2-8 months of age. The elevated Aß levels are associated with the development of amyloid deposits in frontal, temporal, and entorhinal cortex (EC), hippocampus, presubiculum, subiculum, and cerebellum. Some mice even develop the signature "Maltese cross" pattern of amyloid deposits seen in human AD.

Behavior and age of phenotype:

9-10 month old tg mice demonstrate memory deficits in Y mazes and MWM. These behavior alterations correlate with the development of amyloid plaques and with impaired long-term potentiation in both the CA1 and dentate gyrus regions of the hippocampus. These transgenic mice also show a significant microglial response to the amyloid plaques with an increase in both number and area.

Availability

Conditions of use:
For research purposes only. For breeding must have a Research Crossbreeding Agreement with Taconic. No distribution to third parties.

Patent:
5,877,399. Transgenic mice expressing APP-Swedish mutation develop progressive neurologic disease. Karen Hsiao et al.

Contact: Taconic Datasheet. Stock #001349.

References

Primary:

Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G. Correlative memory deficits, A͎ elevation, and amyloid plaques in transgenic mice. Science. 1996 Oct 4 ; 274(5284):99-102. Abstract.

Associated:

Rossner S, Schulz I, Zeitschel U, Schliebs R, Bigl V, Demuth HU. Brain prolyl endopeptidase expression in aging, APP transgenic mice and Alzheimer's Disease. Neurochem Res. 2005 Jun;30(6-7):695-702.

Zhao Z, Ho L, Wang J, Qin W, Festa ED, Mobbs C, Hof P, Rocher A, Masur S, Haroutunian V, Pasinetti GM. Connective tissue growth factor (CTGF) expression in the brain is a downstream effector of insulin resistance-associated promotion of Alzheimer's disease beta-amyloid neuropathology. FASEB J. 2005 Sep 26;

Ribe EM, Perez M, Puig B, Gich I, Lim F, Cuadrado M, Sesma T, Catena S, Sanchez B, Nieto M, Gomez-Ramos P, Moran MA, Cabodevilla F, Samaranch L, Ortiz L, Perez A, Ferrer I, Avila J, Gomez-Isla T. Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice. Neurobiol Dis. 2005 Aug 23;

Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, Bacskai BJ, Hyman BT. Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci. 2005 Aug 3;25(31):7278-87.

McGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C, Skipper L, Murphy MP, Beard J, Das P, Jansen K, Delucia M, Lin WL, Dolios G, Wang R, Eckman CB, Dickson DW, Hutton M, Hardy J, Golde T. Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron. 2005 Jul 21;47(2):191-9.

Wu ZL, Ciallella JR, Flood DG, O'kane TM, Bozyczko-Coyne D, Savage MJ. Comparative analysis of cortical gene expression in mouse models of Alzheimer's disease. Neurobiol Aging. 2005 May 28;

Zohar O, Pick CG, Cavallaro S, Chapman J, Katzav A, Milman A, Alkon DL. Age-dependent differential expression of BACE splice variants in brain regions of tg2576 mice. Neurobiol Aging. 2005 Aug-Sep;26(8):1167-75.

Lee JH, Lau KF, Perkinton MS, Standen CL, Rogelj B, Falinska A, McLoughlin DM, Miller CC. The neuronal adaptor protein X11beta reduces amyloid beta-protein levels and amyloid plaque formation in the brains of transgenic mice. J Biol Chem. 2004 Nov 19;279(47):49099-104.

Middei S, Geracitano R, Caprioli A, Mercuri N, Ammassari-Teule M. Preserved fronto-striatal plasticity and enhanced procedural learning in a transgenic mouse model of Alzheimer's disease overexpressing mutant hAPPswe. Learn Mem. 2004 Jul-Aug;11(4):447-52.

Fonseca MI, Zhou J, Botto M, Tenner AJ. Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J Neurosci. 2004 Jul 21;24(29):6457-65.

Krezowski J, Knudson D, Ebeling C, Pitstick R, Giri RK, Schenk D, Westaway D, Younkin L, Younkin SG, Ashe KH, Carlson GA. Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression. Hum Mol Genet. 2004 Sep 15;13(18):1989-97.

Wilcock DM, Rojiani A, Rosenthal A, Levkowitz G, Subbarao S, Alamed J, Wilson D, Wilson N, Freeman MJ, Gordon MN, Morgan D. Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition. J Neurosci. 2004 Jul 7;24(27):6144-51.

Stern EA, Bacskai BJ, Hickey GA, Attenello FJ, Lombardo JA, Hyman BT. Cortical synaptic integration in vivo is disrupted by amyloid-beta plaques. J Neurosci. 2004 May 12;24(19):4535-40.

Reddy PH, McWeeney S, Park BS, Manczak M, Gutala RV, Partovi D, Jung Y, Yau V, Searles R, Mori M, Quinn J. Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease. Hum Mol Genet. 2004 Jun 15;13(12):1225-40.

Das P, Howard V, Loosbrock N, Dickson D, Murphy MP, Golde TE. Amyloid-beta immunization effectively reduces amyloid deposition in FcRgamma-/- knock-out mice. J Neurosci. 2003 Sep 17;23(24):8532-8.

Lee JH, Lau KF, Perkinton MS, Standen CL, Shemilt SJ, Mercken L, Cooper JD, McLoughlin DM, Miller CC. The neuronal adaptor protein X11alpha reduces Abeta levels in the brains of Alzheimer's APPswe Tg2576 transgenic mice. J Biol Chem. 2003 Nov 21;278(47):47025-9.

Ishizawa T, Sahara N, Ishiguro K, Kersh J, McGowan E, Lewis J, Hutton M, Dickson DW, Yen SH. Co-localization of glycogen synthase kinase-3 with neurofibrillary tangles and granulovacuolar degeneration in transgenic mice. Am J Pathol. 2003 Sep;163(3):1057-67.

Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G.Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci. 2003 Aug 20;23(20):7504-9.

Wilcock DM, DiCarlo G, Henderson D, Jackson J, Clarke K, Ugen KE, Gordon MN, Morgan D. Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation. J Neurosci. 2003 May 1;23(9):3745-51.

Bacskai BJ, Kajdasz ST, McLellan ME, Games D, Seubert P, Schenk D, Hyman BT. Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy. J Neurosci. 2002 Sep 15;22(18):7873-8.

Maynard CJ, Cappai R, Volitakis I, Cherny RA, White AR, Beyreuther K, Masters CL, Bush AI, Li QX. Overexpression of Alzheimer's disease amyloid-beta opposes the age-dependent elevations of brain copper and iron. J Biol Chem. 277(47):44670-6, 2002.

Stein TD, Johnson JA. Lack of neurodegeneration in transgenic mice overexpressing mutant amyloid precursor protein is associated with increased levels of transthyretin and the activation of cell survival pathways. J Neurosci. 2002 Sep 1;22(17):7380-8.

Pratico D, Uryu K, Sung S, Tang S, Trojanowski JQ, Lee VM. Aluminum modulates brain amyloidosis through oxidative stress in APP transgenic mice. FASEB J. 2002 Jul;16(9):1138-40.

Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY. Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice.Proc Natl Acad Sci U S A. 2002 May 28;99(11):7705-10.

Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, Carlson GA, Younkin SG, Ashe KH. The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease. J Neurosci. 2002 Mar 1;22(5):1858-67.

Gau JT, Steinhilb ML, Kao TC, D'Amato CJ, Gaut JR, Frey KA, Turner RS. Stable beta-secretase activity and presynaptic cholinergic markers during progressive central nervous system amyloidogenesis in Tg2576 mice. Am J Pathol. 2002 Feb;160(2):731-8.

Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci. 2001 Nov 1;21(21):8370-7.

Sigurdsson EM, Scholtzova H, Mehta PD, Frangione B, Wisniewski T. Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice. Am J Pathol. 2001 Aug;159(2):439-47.

Irizarry MC, Locascio JJ, Hyman BT. beta-site APP cleaving enzyme mRNA expression in APP transgenic mice: anatomical overlap with transgene expression and static levels with aging. Am J Pathol. 2001 Jan;158(1):173-7.