They may not reflect what really happens in the brains of Alzheimer's patients.A research has shown that in some mouse breeds, drugs that had been shown to reduce levels of a toxic protein called amyloid beta had only minor or no effect.
“Testing drugs against Alzheimer's disease on animals is not easy because animals don’t develop the disease,” Sascha Weggen, Professor of Molecular Neuropathology at Heinrich-Heine-University, Duesseldorf, Germany says. Most compounds that are tested against Alzheimer's disease (AD) try to prevent brain proteins called amyloid beta peptides from aggregating and forming plaques, which is a hallmark of the disease.
Amyloid beta peptides result from the breakdown of a protein called amyloid precursor protein (APP) by enzymes called beta-secretase and gamma-secretase. In AD patients, the breakdown of APP molecules is increased, leading to an excess of amyloid beta peptides. To reduce the amount of amyloid beta, chemical compounds are tested for their ability to block gamma-secretase or reduce its activity.
Before being administered in humans, the compounds are tested on mice that carry mutations in the gene that produces APP proteins, leading to an excess of APP, which, when cleaved, generate too many amyloid beta peptides.
New mouse breeds have recently been created to also carry mutant genes for a protein called presenilin, which is part of gamma-secretase. These mutations cause gamma-secretase to cut APP in a slightly different way than in normal mice, which also leads to an accumulation of amyloid beta peptides. Mouse breeds that carry both APP and presenilin mutations develop symptoms earlier and the disease has a more aggressive course.
Surprisingly, Weggen and colleagues noticed that chemical compounds that had been shown to reduce amyloid beta deposits did not affect some of these new mouse breeds. “Our study shows that these mouse breeds may not reflect what may really happen in the brains of Alzheimer’s patients if they were treated with such compounds in future clinical studies,” Weggen says. “These compounds may seem to be ineffective on these mice, while it’s actually the mouse breed that is to blame.” The researchers suggest using mouse breeds that carry only APP mutations for further studies of compounds that block or reduce the activity of gamma-secretase.
MEDICA.de; Source: American Society for Biochemistry and Molecular Biology