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


  1. As reported in our J. Neurosci. paper, the 5XFAD mice display obvious neuron loss of large pyramidal neurons in layer 5 of the cortex and in the subiculum at 9 months of age. It appears that the neuron loss may be related to an increase in p25, the activating subunit of Cdk5, which has been shown by Li-Huei Tsai and colleagues to cause neurodegeneration in vivo. We are undertaking a stereological study of 5XFAD mice of various ages to determine when neuron loss begins and the rate at which it progresses in this mouse model, but data from this study are not yet ready to report. In a related investigation, as a collaboration with Masuo Ohno and John Disterhoft, we have mated our 5XFAD mice with BACE1 knockout mice and have demonstrated that genetic ablation of BACE1 and the resulting abrogation of cerebral Aβ results in the prevention of neuron loss in the bigenic animals. These data indicate that Aβ is the cause of neuronal degeneration and death in 5XFAD mice, rather than an artifact resulting from mutant APP and PS1 overexpression. Our work strongly suggests that Aβ is ultimately responsible for neuron loss in AD, a conclusion that has met with a fair amount of debate and controversy in the past.

    In a pilot study, we noted that female 5XFAD mice showed elevated cerebral IL-1β levels at 9 months of age as compared to age-matched 5XFAD males, suggesting a more pronounced inflammatory reaction in female transgenic brains. We did not include this data in our J. Neurosci. article, because we are still investigating the IL-1β increase and plan to determine its basis for a future report. We speculate that the rise in IL-1β may involve some female-specific and age-dependent response to the massive Aβ42 deposition that occurs in this mouse model. Women are known to have an increased risk of developing AD, but it is unclear whether this elevated female risk involves greater IL-1β levels and inflammation in the brains of women as compared to men. Clearly, more work in this area needs to be done to understand the relationship, if any, of the IL-1β increase in 5XFAD female mice and the elevated AD risk of women.

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News Citations

  1. SfN: Where, How Does Intraneuronal Aβ Pack Its Punch? Part 1

Paper Citations

  1. . 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.
  2. . 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.

Further Reading

No Available Further Reading

Primary Papers

  1. . 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.