If doubling the number of FAD mutations can exacerbate Aβ pathology (see Eckman et al., 1997 and Citron et al., 1998), what about boosting the mutations fivefold? Such a model of Alzheimer disease (AD), first reported in our SfN meeting coverage last year, is described in the October 4 Journal of Neuroscience. Robert Vassar and colleagues at Northwestern University, Chicago, Illinois, show that 5XFAD transgenic mice—expressing human amyloid precursor protein (APP) with Swedish (K670NM671L), Florida (I716V), and London (V717I) mutations, and human presenilin with two mutations, M146L and L286V—have not only rampant and early deposition of plaques, but intraneuronal Aβ aggregates as well. The mice display other pathologies associated with AD, including synapse and neuron loss, elevated p25, and impaired memory. The combination of pathologies makes the mice a particularly attractive model for study, especially given the recent preponderance of evidence linking intraneuronal Aβ with toxicity, and the speed with which the symptoms appear. For more on this model and intracellular Aβ, see our original meeting coverage.—Tom Fagan
- Eckman CB, Mehta ND, Crook R, Perez-tur J, Prihar G, Pfeiffer E, Graff-Radford N, Hinder P, Yager D, Zenk B, Refolo LM, Prada CM, Younkin SG, Hutton M, Hardy J. A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43). Hum Mol Genet. 1997 Nov;6(12):2087-9. PubMed.
- Citron M, Eckman CB, Diehl TS, Corcoran C, Ostaszewski BL, Xia W, Levesque G, St George Hyslop P, Younkin SG, Selkoe DJ. Additive effects of PS1 and APP mutations on secretion of the 42-residue amyloid beta-protein. Neurobiol Dis. 1998 Aug;5(2):107-16. PubMed.
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- 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. 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. 2006 Oct 4;26(40):10129-40. PubMed.