Sci. Aging Knowl. Environ., 4 February 2004
Vol. 2004, Issue 5, p. tg1
GENETICALLY ALTERED MICE
Amyloid Precursor Protein (APP) Transgenic Mice (Tg2576 Mice)
||Amyloid precursor protein (APP) transgenic mice (Tg2576 mice).
||Tg(HuAPP695 SWE)2576 was originally generated in a hybrid C57Bl/6J x SJL background. The transgenic mice were backcrossed to C57Bl/6J for two generations and then crossed to C57Bl/6J x SJL F1 hybrid.
||The gene encoding the 695-amino acid isoform of a mutant form of human amyloid precursor protein (APP) was inserted into mice using a hamster prion protein cosmid vector, in which APP replaced the prion protein open reading frame. Expression of APP is driven by the hamster prion protein gene promoter.
|Type of change
||In this strain, an Alzheimer's disease (AD)-associated mutant variant of human APP (Lys670Asn670, Met671Leu671) is overexpressed. The variant was found in a Swedish family with early-onset AD.
|Nature of protein
||APP is a large membrane-spanning protein that is cut by proteases into several smaller peptides, including the beta-amyloid peptide found in neuritic plaques in AD patients.
||These mice express high levels of mutant beta-amyloid and, with increasing age, develop both substantial amyloid plaque load and memory deficits.
|Corresponding human phenotype
||In Alzheimer's disease, amyloid plaques accumulate in the cerebral cortex, hippocampus, and amygdala and correlate with memory deficits.
||K. Hsiao, P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, G. Cole, Correlative memory deficits, beta-amyloid elevation, and amyloid plaques in transgenic mice. Science 274, 99-102 (1996).
||Tg2576 mice are commercially available from Taconic Animal Models, Germantown, NY, USA (www.Taconic.com/anmodels/001349.htm). This is the APP microinjected mouse model [B6;SJL-Tg(APPSWE)2576Kha]. Order model no.: 001349-T (hemizygous); 001349-W (nontransgenic control).
||With increasing age, Tg2576 mice also exhibit increased lipid peroxidation in brain tissues. Sung et al. (2003) fed 8 to 10 international units of vitamin E per day to two groups of Tg2576 mice. In the first group, feeding started at 5 months of age and continued to 13 months of age; and in the second group, feeding started at 14 months of age and continued to 20 months of age. Mice fed vitamin E at young ages exhibited less lipid peroxidation, lower amounts of beta-amyloid, and less plaque formation relative to placebo-fed mice. Mice fed vitamin E at older ages exhibited less lipid peroxidation but did not display significantly different amounts of beta-amyloid or plaque formation as compared to control mice. The authors suggest that oxidative stress might play a causal role in the amyloid cascade, a role that must be suppressed early in life to prevent plaque deposition and associated damage.
||Related transgenic mice:
Mice that are transgenic for both HuAPP695 SWE and human variants of presenilin 1 (A246E or DeltaE9) exhibit even more extreme AD-like pathology than Tg2576 mice.
Triple-Transgenic Alzheimer's Disease Model Mice
SAGE KE's Genes/Interventions database:
amyloid cascade hypothesis
February 4, 2004
- P. F. Chapman, G. L. White, M. W. Jones, D. Cooper-Blacketer, V. J. Marshall, M. Irizarry, L. Younkin, M. A. Good, T. V. P. Bliss, B. T. Hyman, et al., Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat. Neurosci. 2, 271-276 (1999).[CrossRef][Medline]
- K. Hsiao, P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, G. Cole, Correlative memory deficits, beta-amyloid elevation, and amyloid plaques in transgenic mice. Science 274, 99-102 (1996).[Abstract/Free Full Text]
- D. Praticó, K. Uryu, S. Leight, J. Q. Trojanowski, V. M.-Y. Lee, Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J. Neurosci. 21, 4183-4187 (2001).[Abstract/Free Full Text]
- S. Sung, Y. Yao, K. Uryu, H. Yang, V. M.-Y. Lee, J. Q. Trojanowski, D. Praticó, Early vitamin E supplementation in young but not aged mice reduces beta-amyloid levels and amyloid deposition in a transgenic model of Alzheimer's disease. FASEB J., 4 December 2003 [e-pub ahead of print]. [Abstract].
Amyloid Precursor Protein (APP) Transgenic Mice (Tg2576 Mice). Sci. Aging Knowl. Environ. 2004
(5), tg1 (2004).