New Class of Drugs May Fight Alzheimer's

By Steven Reinberg
12 june 2008-- A class of drugs called gamma-secretase modulators shows potential for treating Alzheimer's disease, a new study suggests.
A hallmark of Alzheimer's is so-called amyloid plaque, which develops tangles in the brain. The gamma-secretase modulators reduce the production of long pieces of amyloid beta protein that stick together and form clumps. At the same time, the drugs increase the production of shorter amyloid beta that blocks longer amyloid beta from sticking together, the researchers explained.
"We have discovered a novel mechanism of action for a class of drugs that are currently being tested as Alzheimer's disease therapeutics," said lead researcher Dr. Todd E. Golde, an associate professor at the Mayo Clinic Department of Neuroscience, in Jacksonville, Fla.
These new drugs don't work in the same way that many other drugs do, Golde said. "Sometimes we think of drugs as magic bullets targeting a single entity, but this drug, by the way it works, could have three consequences that could have a benefit for Alzheimer's disease," he said.
While the new compounds decrease the production of long chains of amyloid beta, Golde said, "Surprisingly, they increase the presence of shorter chains of amyloid beta, which we think actually prevents the accumulation of longer chains of amyloid beta."
"In a short form, amyloid beta is harmless as far as we know," he added. "So you sort of get three bangs for your buck."
"This finding could tell us how drugs for Alzheimer's disease already in clinical trials may be working," Golde said. One of the modulator drugs, tarenflurbil (Flurizan), was in a just-completed phase III clinical trial, and the results should be available this summer, he said.
The latest findings are published in the June 12 edition of Nature.
One expert thinks the new research could produce a drug that could fight the development of amyloid plaque in two ways.
"This is interesting and unexpected," said Dr. Sam Gandy, chairman of the Alzheimer's Association's National Medical and Scientific Advisory Council. "This suggests that it might be possible to design or identify compounds that both modulate generation of amyloid beta and at the same time modulate accumulation of amyloid beta."
Until now, anti-amyloid drugs have fallen into three broad classes: immunotherapies, anti-aggregation compounds, and secretase modulators, Gandy said. "The new work suggests that there exist single drugs that possess both of the latter two activities, thereby supplying an anti-amyloid double whammy," he said.
Another expert thinks this avenue of attack on amyloid plaque looks promising.
"Chronic intake of NSAIDs like ibuprofen appears to reduce the risk of Alzheimer's," said Greg M. Cole, associate director of the Alzheimer's Disease Research Center at UCLA David Geffen School of Medicine.
"A subset of NSAIDs that the authors call gamma-secretase modulators appears to reduce the accumulation of the stickiest form of beta amyloid protein that is believed to aggregate and cause the disease," Cole said. "This means that the known protective NSAIDs may be a double threat against Alzheimer's and help protect against it if they are taken early for prevention."