JAX Notes June 01, 2004

APP mouse models for Alzheimers disease research

Genetically engineered mice provide a valuable resource for Alzheimer's disease (AD) research, both for understanding disease mechanisms and for testing potential therapies. In 2004, the Induced Mutant Resource at The Jackson Laboratory added four models to the growing number of AD-related strains within the Alzheimer's Disease Mouse Model Resource (ADMMR).

Familial AD (FAD) is associated with mutations that lead to production of Aβ42 peptide, a constituent of the characteristic amyloid plaques diagnostic of AD. These mutations occur at the proteolytic cleavage sites in the gene encoding the amyloid-β precursor protein (APP), and in the genes for presenilins 1 and 2 (PSEN1 and PSEN2), enzymes involved in APP cleavage.

Dr. Lennart Mucke of the Gladstone Institute of Neurological Disease created (Stock Number 004661) B6.Cg-Tg(PDGFB-APPSwInd)20Lms/J (or "J20"), so it expresses a mutant form of human APP bearing both the Swedish (K670N/M671L) and the Indiana (V717F) mutations (APPSwInd). APP expression is directed to neurons under the control of a human platelet-derived growth factor β polypeptide (PDGFB) promoter.

The control strain, (Stock Number 004662) B6.Cg-Tg(PDGFB-APP)5Lms/J (or "I5"), uses a transgenic construct containing the wild-type human APP gene under the same promoter. The I5 line was selected because it displays similar expression levels to the B6.Cg-Tg(PDGFB-APPSwInd)20Lms/J line. Both the mutant and control lines originated on a mixed C57BL/6 and DBA/2 background and have been backcrossed onto the C57BL/6J background. Both strains are maintained with hemizygous matings or as hemizygous colonies.

Hemizygous transgenic mice express immunodetectable transgene product in cerebral neurons, with the highest level of expression occurring in the neocortex and hippocampus. Enzyme-linked immunosorbent assay (ELISA) analysis determined that the mutant line produced more Aβ than the control. In mutant transgenic mice, diffuse Aβ deposition in the dentate gyrus and neocortex forms by five to seven months of age, and amyloid deposition is progressive.

All mutant transgenic mice exhibit plaques by age eight to 10 months. No amyloid plaques were detected in the control strain up to 24 months of age. Both lines display a loss of presynaptic terminals, suggesting that plaque-independent Aβ may be synaptotoxic and that neuronal deficits may precede plaque formation (Mucke et al., 2000).

These two models represent a useful resource for determining the mechanism of plaque formation and the role of plaques in AD-related neuropathology. Additionally, they may be used to explain how plaque-independent Aβ deposition can lead to synaptic loss. The strain expressing wild-type APP may serve as a model for sporadic AD, while the mutated APP transgenic is a useful model for FAD.

These strains are now being distributed as breeder pairs or as small numbers of individual mice. Licensing restrictions apply to all strains. The APP transgenic strains are available to non-profit research institutions for non-commercial research only. To obtain any of these mice, please call Customer Service at 800.422.MICE (6423) or 207.288.5845. For more information on The Jackson Laboratory's resources related to Alzheimer's disease, see www.jax.org/jaxmice/models/neurodegeneration.html.

More information and resources to further the study of AD can be found at the Alzheimer Research Forum (www.alzforum.org).

References:

Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, et al. 1996. Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ1-42/1-40 ratio in vitro and in vivo. Neuron 17:1005-13.

Guo Q, Fu W, Sopher BL, Miller MW, Ware CB, Martin GM, Mattson MP. 1999. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med 5:101-6.

Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L. 2000. High-level neuronal expression of Aβ1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20:4050-8.