JACKSONVILLE, Fla., - Researchers at Mayo Clinic in Jacksonville, Fla., have successfully bred mice exhibiting amyloid plaques and neurofibrillary tangles, the two key pathologic hallmarks of Alzheimer's disease (AD). Until now, an animal model that exhibited both of these brain lesions did not exist.
The breakthrough is expected to provide investigators a better animal model in which to test therapies aimed at preventing or halting progression of the degenerative brain disease affecting approximately 4 million Americans. The Mayo Clinic team of Michael Hutton, Ph.D.; Dennis Dickson, M.D.; Jada Lewis, Ph.D.; Shu-Hui Yen, Ph.D.; and Eileen McGowan, Ph.D., will publish its work in the August 24 issue of Science.
Many researchers studying potential causes of AD suspect that when amyloid beta protein deposits in the brain to form plaques, the phenomenon sets off a cascade of pathology that leads to AD. Somewhere in the disease process neurofibrillary tangles, caused by abnormal tau protein, develop in the brain, and brain cells die as well. No one has proven whether the plaques lead to tangles or vice versa.
The Mayo group bred a mouse they genetically engineered to develop neurofibrillary tangles with a mouse similarly engineered to develop amyloid plaques. Hutton believes the resulting double transgenic mouse strengthens the amyloid cascade hypothesis. "The evidence we've got is consistent with that," Hutton says. "What we saw in the crossbred mice were not only plaques and tangles, but the tangle pathology was enhanced in regions where the plaques occurred." And he says the lesions occurred in regions of the brain first affected by AD. "If we were simply seeing random changes in tangle pathology in areas that weren't related to amyloid or Alzheimer's disease, this would not be so interesting," Hutton says. "The key point is we see the enhanced tangle pathology in areas that are affected in Alzheimer's."
The Hutton team's double transgenic mouse will provide researchers a more complete model of human AD. Hutton says biochemical changes in tau that occur in humans with the disease also occur in these mice.
Researchers at Mayo have now begun to test the recently developed amyloid vaccine on their double transgenic mice to see if the vaccine prevents tangle formation and brain cell death.
They also hope to breed an even better AD mouse model by using mice that deposit amyloid earlier in their lifespan than the animals they are currently breeding. "One of the biggest problems we have is that the tau mice don't live all that long," Hutton says. "They start to die at an age when the pathology in the amyloid mice hasn't reached its final stage. We're in the process of trying to get mice that deposit amyloid more rapidly. This will basically let us compress the time frame of these studies, allowing us to look at mice that have lots of amyloid together with tau pathology, and to do it all within the lifespan of these crossed animals."