New Strains Added to the Alzheimer's Disease Mouse Model Resource

JAX® NOTES Issue 507, Fall 2007

The Alzheimer's Disease Mouse Model Resource currently distributes 45 mouse strains for Alzheimer's disease (AD) research; 10 more models are under development. Below, 3 important new models are described:

B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/J
(006554)

This "5X FAD" strain was developed in the laboratory of Bob Vassar at Northwestern University. It carries 5 familial AD mutations, including a human amyloid precursor protein (APP) transgene with the Swedish, Florida, and London mutations, and a human presenilin (PSEN1) transgene carrying the M146L and L286V mutations (Oakley et al. 2006). These mutations lead to altered cleavage of the APP protein by the presenilin enzyme complex and to an increased production of the toxic peptide Aβ42 relative to the nontoxic Aβ40. By 6 weeks of age, this strain displays elevated levels of Aβ42 and amyloid deposits and ongoing age-dependent amyloid pathology. By 4 months of age, synaptic loss, neurodegeneration, neuroinflammation, and learning and memory deficits are evident. Compared to that of other AD mouse models, the AD phenotype of this model is unusually early. Recently, this model was used to demonstrate that expression of the beta-site APP cleaving enzyme 1 (Bace1) gene is required for the AD phenotype (Ohno et al. 2007) and that BACE1 interacts with Aβ in a positive feedback loop to accelerate AD pathology (Zhao et al. 2007). Note: Due to restrictions from the originating institution, this model will be available only for academic use.

B6;C3-Tg(Prnp-ITM2B/APP695*42)A12Emcg/J
(007002)

B6;C3-Tg(Prnp-ITM2B/APP695*40)1Emcg/J
(006880)

These two strains were constructed by Eileen McGowan and Todd Golde at the Mayo Clinic, Jacksonville, Florida. To generate high levels of specific Aβ fragments without overexpressing the entire APP molecule, McGowan and Golde cleverly placed a transgenic fusion protein with an Aβ peptide next to a cleavage site. Endogenous proteases liberate the peptide. The first, or "BRI- Aβ42," strain expresses the Aβ42 peptide and develops amyloid plaques and cerebral amyloid angiopathy. Mating this strain to another APP transgenic strain produces offspring with drastically increased amyloid deposits (Lewis et al. 2001; McGowan et al. 2005). The second, or "BRI- Aβ40," strain expresses high levels of the Aβ40 peptide but exhibits no AD phenotype. In fact, mating this strain to a transgenic line overexpressing human APP produces offspring with fewer amyloid plaques than in mice carrying just the APP transgene, suggesting that the Aβ40 peptide can ameliorate AD symptoms (Kim et al. 2007). Note: Use of these two strains by academic institutions will be unrestricted; for-profit institutions will need a license from the Mayo Foundation for Medical Education and Research.

We encourage you to register interest in these strains at their respective strain data sheets (links provided in text above). By doing so, you will receive advance notice of their availability and help us size breeding colonies to best meet demand.

References

Kim J, Onstead L, Randle S, Price R, Smithson L, Zwizinski C, Dickson DW, Golde T, McGowan E. 2007. Abeta40 inhibits amyloid deposition in vivo. J Neurosci 27:627-33.

Lewis, PA, Piper S, Baker M, Onstead L, Murphy MP, Hardy J, Wang R, McGowan E, and Golde TE. 2001. Expression of BRI-amyloid beta peptide fusion proteins: a novel method for specific high-level expression of amyloid beta peptides. Biochim Biophys Acta 1537:58-62.

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. 2005. Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47:191-9.

Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R. 2006. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 26:10129-40.

Ohno M, Cole SL, Yasvoina M, Zhao J, Citron M, Berry R, Disterhoft JF, Vassar R. 2007. BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26:134-145.

Zhao J, Fu Y, Yasvoina M, Shao P, Hitt B, OÕConnor T, Logan S, Maus E, Citron M, Berry, R, Binder L, Vassar R. (2007). Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer's disease pathogenesis. J Neurosci 27:3639-49.