A new finding by USF researchers may give scientists a new target for developing drugs to fight Alzheimer's and could assist in early detection.
By STEPHEN NOHLGREN
Published June 27, 2003
TAMPA - With names like GluR1 and Zif268, these mouse genes are anything but glamorous. But someday they may unlock secrets to Alzheimer's disease.
University of South Florida researchers have discovered that six genes critical to making memories tend to shut down when lab mice develop the telltale markers of Alzheimer's disease in their brains.
Scientists have long suspected that these markers, called amyloid plaques, destroy brain cells and muddle communication between neurons. The USF study refines those theories by focusing on the role of genes, which instruct cells how to perform.
The results, published Thursday in the online version of the Journal of Neuroscience, showed an abnormal reduction in memory genes only in brain areas where the plaques occurred. Brain areas free of plaques showed normal gene levels.
A separate study of human brains from deceased Alzheimer's victims showed similar reductions of the same genes.
The findings are important for two reasons.
Memory loss is an early symptom of Alzheimer's. Understanding the relationship between plaques and memory genes could produce breakthroughs at early stages, where treatments would do the most good.
The study also gives researchers a new target for developing anti-Alzheimer's drugs. Several current drug trials already aim to prevent plaques or clean them up.
Now new types of drugs might be developed to try to maintain normal levels of memory genes even when plaques can't be eliminated.
Professor David Morgan, director of USF's Alzheimer's Disease Research Laboratory, compared the future of dementia drugs to the treatment of heart disease. "We have delayed 30 years the time people die of heart disease," Morgan said. "It isn't one drug. It's drugs that control high blood pressure, drugs that control cholesterol levels, drugs to control blood clotting. We haven't eliminated the disease, but we've helped people live longer, healthier lives.
"The same thing is going to happen with Alzheimer's disease," Morgan said. "Some people will respond nicely to drugs that will stop the production of amyloid, some will respond to the drugs that remove amyloid, and still others will respond to drugs that block the effects of amyloid."
Morgan predicted that such drugs would become available in three to five years.
The research was funded by a $2.2-million, five-year grant from the National Institute on Aging. The scientists compared the genetic makeup of normal mice with mice specially bred to develop Alzheimer's-like symptoms at 17 to 18 months of age.
About 10,000 genes were examined. Morgan said he expected to see abnormalities with genes that dictate the structure of brain cells, leading to cell destruction. Instead, the six genes that showed up as abnormal all related to the functioning of neuron synapses - the connection points where brain cells communicate to each other. Synaptic communication is critical to forming memory.
Normal mice that are placed in stimulating new environments show elevated levels of these memory genes. In other words, the genes told the brain cells to start learning new stuff. Memory genes of the Alzheimer's mice didn't elevate as much. They weren't processing the new information as well.
The Alzheimer's mice were bred at USF. The gene analysis was performed by Incyte Genomics in Palo Alto, Calif.
Mice and humans share the great majority of their genes, including the six genes highlighted in the study. By using mice, researchers can kill them at any time and examine brain changes early in the progression of the disease.
"This is one of the very first times that genes associated with development of plaques have really been ... analyzed and looked at in any detailed way," said Dr. Stephen Snyder, who oversaw the study for the NIA.
"These (genes) may be involved in the earliest manifestations of the disease. They may be the root cause of some of that senile forgetfulness."
Potential drugs might block whatever mechanism causes the amyloid plaques to shut down the memory genes. Other drugs might simply boost production of these genes, although doctors would have to be careful not to create too many new memories, Morgan said.
"I'd be afraid you might remember everything that happened today really, really well, at the expense of what happened yesterday."
