This study reports a novel transgenic mouse line expressing five different familial Alzheimer disease associated mutations in the human APP and presenilin 1 genes. This greatly enhanced the onset of amyloid pathology, which was readily detectable at 2 months of age. The mice also exhibited neuronal and synaptic loss, which is accompanied by a learning impairment. The most interesting aspects of this study are that the 5XFAD mice produced Aβ42 almost exclusively and developed intraneuronal Aβ, which appeared to temporally and spatially precede the detection of extracellular plaques. This observation supports the notion that intraneuronal Aβ accumulation precedes the extracellular plaques and is closely associated with other pathologies, such as neuronal demise. The relevance of intraneuronal Aβ has been disputed as it was not originally detected in AD mouse models and postmortem AD brains. However, using improved antibodies and techniques, recent studies in postmortem human brains (Gouras et al., 2000; Takahashi et al., 2002) and mouse models (Oddo et al., 2003; Casas et al.,...  Read more

This study reports a novel transgenic mouse line expressing five different familial Alzheimer disease associated mutations in the human APP and presenilin 1 genes. This greatly enhanced the onset of amyloid pathology, which was readily detectable at 2 months of age. The mice also exhibited neuronal and synaptic loss, which is accompanied by a learning impairment. The most interesting aspects of this study are that the 5XFAD mice produced Aβ42 almost exclusively and developed intraneuronal Aβ, which appeared to temporally and spatially precede the detection of extracellular plaques. This observation supports the notion that intraneuronal Aβ accumulation precedes the extracellular plaques and is closely associated with other pathologies, such as neuronal demise. The relevance of intraneuronal Aβ has been disputed as it was not originally detected in AD mouse models and postmortem AD brains. However, using improved antibodies and techniques, recent studies in postmortem human brains (Gouras et al., 2000; Takahashi et al., 2002) and mouse models (Oddo et al., 2003; Casas et al., 2004; Billings et al., 2005) have demonstrated the presence of intraneuronal Aβ. The current study, in conjunction with the previous mouse model studies, demonstrates a close association of intraneuronal Aβ deposition with neuronal death and cognitive decline.

View all comments by Li-Huei Tsai

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...  Read more

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.

View all comments by Robert Vassar