Modified Mice Test Alzheimer's Disease Drugs
Developing therapeutic drugs to stop the formation of the lesions, called amyloid plaques, and to remove them from the brain has become the focus of intense research efforts by pharmaceutical companies. Unfortunately, methods to test the efficacy of the drugs are limited as is the access to test results given to outside researchers.
Now neuroscientist Joanna L. Jankowsky, a senior research fellow in the laboratory of Henry A. Lester, Bren Professor of Biology at the California Institute of Technology, in collaboration with David R. Borchelt at the University of Florida, Gainesville, and colleagues at Johns Hopkins School of Medicine, Mayo Clinic Jacksonville, and the National Cancer Institute, have created a strain of genetically engineered mice that offers an unprecedented opportunity to test these new drugs and provides striking insight into possible future treatment for the disease.
A paper about the mouse model was published November 15 in the international open-access medical journal PLoS Medicine (www.plosmedicine.org).
The amyloid-beta peptide is something of an enigma. It is known to be produced normally in the brain and to be churned out in excess in Alzheimer's disease. But researchers don't know exactly what purpose the molecule usually serves--or, indeed, what happens to dramatically raise its concentration in the Alzheimer's brain.
The peptide is created when a molecule called amyloid precursor protein (APP) is snipped in two places, at the front end by an enzyme called beta-APP cleaving enzyme, and at the back end by an enzyme called gamma-secretase. If either of those two cuts is blocked, the amyloid-beta protein won't be released--and plaque won't build up in the brain.
To prevent plaques from accumulating, drug companies have been experimenting with compounds that inhibit one or the other of the enzymes, thereby blocking the release of amyloid-beta. Jankowsky and her colleagues decided to test how well this approach to treating Alzheimer's disease will work. Because they lacked access to the drugs themselves, they instead engineered a laboratory mouse with two added genes that would mimic the effect of secretase inhibitor treatment. One gene triggered the continuous production of APP in the brain (and thus also the amyloid-beta peptide) leading to substantial plaque deposits in mice as young as six months old. The second gene served as an off-switch to amyloid-beta. The researchers were able to flip the switch at will by adding the antibiotic tetracycline into the mice's food--and when they did so, they also halted all plaque formation.
"The key point here is that we've completely arrested the progression of the pathology," says Jankowsky.
Plaque deposits that had already formed, however, weren't cleared out.
"We can stop the disease from getting worse in these mice, but we can't reverse it," says study co-author David Borchelt, Jankowsky's former postdoctoral research advisor at Johns Hopkins University. "Although it is possible that human brains repair damage better than mouse brains, the study suggests that it may be difficult to repair lesions once they have formed."
One implication of the research is that it suggests that treatment with drugs to stop plaque formation should begin as soon as possible after the disease is diagnosed. "It looks like early intervention would be the most effective way of treating disease," Jankowsky says.
"It was surprising to many people that the plaques didn't go away, but they are really very stable structures," says Jankowsky. It is also possible, some researchers believe, that the plaques themselves aren't damaging. Rather, they may be a sign of the overproduction of amyloid-beta and of the small, free-floating clumps of the peptide that actually cause cognitive problems. "The plaques may simply act as trash cans for what has already been produced," she says. If that is indeed the case, Jankowsky says, then "shutting down the production of amyloid-beta itself would be adequate to reverse cognitive decline."
On the other hand, removal of the plaques could improve cognitive function by allowing neurons that had previously been displaced by the protein deposits to reform and form new neural connections. That is why, the researchers say, an ideal therapy would be one that both prevented the overproduction of new amyloid-beta and cleared out existing deposits.
Drug companies are currently investigating treatment protocols for Alzheimer's disease in which antibodies against the amyloid-beta peptide are directly injected into the body. The antibodies latch onto the molecule and quickly clear it from the brain, along with any plaque deposits that have already formed. However, Jankowsky says, these drugs therapies may not be appropriate for long-term use because of possible side effects. One clinical trial of the antibodies had to be stopped because some patients developed a serious brain inflammation known as encephalitis.
"The upshot of this research is that a combination of approaches may be the best way to tackle Alzheimer's disease," Jankowsky says. "The idea would be to use immunotherapy to acutely reverse the damage, followed by chronic secretase inhibition to prevent it from ever recurring."
For a copy of the paper, go to http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0020355
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Contact: Dr. Joanna L. Jankowsky (626) 395-6884 jlj2@caltech.edu
Kathy Svitil (626) 395-8022 ksvitil@caltech.edu
Visit the Caltech Media Relations Web site at: http://pr.caltech.edu/media
