Sascha Weggen, Professor of Molecular Neuropathology at Heinrich-Heine-University, Duesseldorf, Germany; lead author Eva Czirr, Ph.D. student at the University of Mainz, Germany; and colleagues show in the August 24 issue of the Journal of Biological Chemistry 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 on these mice.
“Testing drugs against AD on animals is not easy because animals don’t develop the disease,” Weggen says. “When using mice, scientists need to artificially induce one or several mutations in the mice and check whether they develop symptoms of the disease that are similar to the human ones. We showed that some of the mice currently bred to develop the disease don’t get better when they receive previously tested drugs.”
The new study was selected as a “Paper of the Week” by the journal’s editors, meaning that it belongs to the top one percent of papers reviewed in significance and overall importance.
Although no cure is yet available for AD – a neurodegenerative disorder affecting around 18 million patients worldwide – scientists are testing various compounds that could become drugs. Most compounds 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. These breeds are probably more reliable than the ones that carry both APP and presenilin mutations, because they cause less aggressive symptoms, Weggen says.
The scientists also propose creating a mouse breed in which the presenilin mutation does not affect both members of the pair of chromosomes that carry the gene – as is the case in current transgenic mice – but only one of the two chromosomes. Such a breed, called a “knock-in” mouse, would reflect the genetic condition of about 5 percent of Alzheimer’s patients.
“Although most AD patients develop the disease after 65, about 5 percent of them are affected much earlier – some as early as their 20s and 30s,” Weggen says. “In these patients, the origin of the disease, called early-onset familiar AD, is mostly genetic, and mutations – including the presenilin one – are carried by only one chromosome in a pair. So far, scientists created only a few mouse breeds with a mutation on one chromosome; such breeds would probably better reflect what actually happens in the brains of AD patients.”
The researchers are now planning to investigate how presenilin mutations cause amyloid beta peptides to be overproduced and to understand how promising chemical compounds block gamma secretase or reduce its function.
“Until now, transgenic mice have been successfully used to understand how AD develops and how to treat it,” Weggen says. “Our study is a reminder that we need to work harder to create mice that reflect Alzheimer’s disease even more accurately, which could bring us closer to actual drugs against this devastating disease.”
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