How reliable are mouse models of Alzheimer disease?
Every animal model for Alzheimer disease is based on the same premise—that overproduction of the amyloid-beta protein somehow triggers a cascade that eventually damages neurons and causes dementia.
There's a risk that there must be some difference between the mice and patients that makes it easier to improve things in mice. Kaj Blennow, Sahlgrenska Academy of Göteborg University
Some of the mice have mutations seen in familial or early-onset Alzheimer disease and form the characteristic plaques seen in diseased brains. Others carry mutations in the protein tau and recreate the tangles, another hallmark of the disease.
“In that capacity, the animal models have been extremely successful and that's no trivial thing,” notes Karen Duff, associate professor of neuroscience at New York University.
Research on the disease, for both mechanisms and treatments, has been based almost exclusively on these mice. But even their staunchest supporters acknowledge that there are glaring flaws.
For instance, only mice that carry two or more mutations reproduce all the physical features of an Alzheimer-addled brain. And most never exhibit the extent of neurodegeneration seen in people afflicted with the disease.
More important, the mice have never shed much light on the mechanisms involved in the disease, such as the relationship between amyloid-beta and tau, the two key molecules.
Because the mice are based on mutations in familial Alzheimer disease, it may be that they only model the rare form of the disease and not the more common sporadic form, suggests Kaj Blennow, professor of clinical neurochemistry at the Sahlgrenska Academy of Göteborg University.
Blennow notes that in the animal models, at least 47 molecules—a bizarre list ranging from cholesterol drugs and painkillers to blueberries and curry spice—have been shown to reduce the number of amyloid plaques.
“Hopefully, some of this is right, but I think there's a risk that there must be some difference between the mice and patients that makes it easier to improve things in mice,” he says. “As I see it, this calls for caution when transferring data from transgenic mice to man.”
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Mandavilli, A. Of mice and men. Nat Med 12, 750 (2006). https://doi.org/10.1038/nm0706-750b
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DOI: https://doi.org/10.1038/nm0706-750b