Researcher works toward solving Alzheimer’s puzzle

Kevin Pang, an associate professor of psychology at Bowling Green State University, has received $800,000 in new funding from the National Institutes of Health for his study of the basal forebrain, one of the earliest regions of the brain affected by Alzheimer’s disease.

BOWLING GREEN, O.—For anyone who has seen a life ravaged by Alzheimer’s disease, or felt its impact on the victim’s caregivers and family, breakthroughs into cause and treatment can’t come soon enough.

Dr. Kevin Pang, associate professor of psychology at Bowling Green State University, is among the researchers seeking insight into the degenerative neurological disorder, and, “optimistically,” he said, the hoped-for breakthroughs may happen in the next 10 years.

Pang, who has received his third National Institutes of Health (NIH) grant for the study of brain function with Alzheimer’s implications, said he wouldn’t be surprised if an effective treatment is available within that time. Clinical studies of potential treatments are in progress now, including some aimed at eliminating the protein that forms the distinctive plaques in the brains of the disease’s victims, he noted.

High incidence of plaques and tangles tells a pathologist conducting an autopsy that the deceased had Alzheimer’s. But whether those indicators are a cause or a result of the disease isn’t known, said Pang, a BGSU faculty member since 1995.

While work continues on treatments for symptoms of Alzheimer’s, increased research attention to stopping or slowing its progression reflects how much more is known about the disorder than 10, or even five, years ago, he said.

He’s looking to further expand understanding at the most basic level, in brain cells, with the help of the NIH grant, which is worth more than $800,000 over four years. The project’s name, “Role of Medial Septum in Memory and Theta Rhythm,” refers to an area of the brain that is part of the basal forebrain—one of the earliest regions of the brain to degenerate in Alzheimer’s, Pang said.

More specifically, one type of cell in the basal forebrain uses a chemical called acetylcholine, and pathologists have noticed that cells containing acetylcholine degenerate rapidly in the disease’s victims, he continued.

All four drugs currently approved for treatment of Alzheimer’s have the same basic mechanism to decrease the degradation of acetylcholine, he explained. They seem to work in some patients, producing a mild increase in acetylcholine, but they’re “not the magic bullet some people had expected,” he said.

At the same time, when acetylcholine-containing cells have been damaged in the basal forebrain of laboratory animals, tests have indicated mild or no impairment, Pang said, pointing out “the paradox” of the animal and human results.

With his latest grant—his two previous NIH awards totaled about $550,000—Pang will be targeting neurons containing GABA, another chemical that cells use to communicate with one another.

What happens to GABA-containing neurons in Alzheimer’s patients is unclear because much of the research focus has been on acetylcholine, he said. Current thinking is that both GABA and acetylcholine must be damaged to see impairment, but he will be trying to learn differences between the two chemicals and how they may be contributing to memory.

Because cells communicate via electrical, as well as chemical, means, target regions of the medial septum will also be monitored for electrical activity, particularly after GABA or acetylcholine damage, Pang said. The damage will be correlated with the behavior of the laboratory animal trying to solve a maze, he added.

Pang has been “very innovative in applying a wide variety of converging methodologies” to his research, according to Dr. Mark Baxter, assistant professor of psychology at Harvard University, who said his BGSU colleague’s study of the basal forebrain has been “very influential in my own work.”

Baxter said the association between damage to the basal forebrain and cognitive impairment in aging and nuerodegenerative disease such as Alzheimer’s has been known for more than 25 years. But “only now are we starting to untangle how the basal forebrain is involved in regulating cognitive functions, including attention, learning and memory,” the Harvard neuroscientist said.

“Kevin’s work in particular is elucidating the contribution of particular classes of nerve cells within the basal forebrain to cognitive function, and is revealing how the function of those cells is regulated by other systems in the brain,” added Baxter, who, as an undergraduate at Johns Hopkins University, took a class taught by Pang, then a postdoctoral fellow.

Where current drugs haven’t been as effective against Alzheimer’s as some had anticipated, gene therapy may provide hope, said Pang, whose Ph.D. in pharmacology is from the University of Colorado Medical Center.

To survive, acetylcholine-containing cells in the basal forebrain require “growth factors,” which are made and released by cells for the survival of their brethren, he said. With one hypothesis holding that the decay of acetylcholine-containing cells in Alzheimer’s patients can be traced to halted production of growth factors, a potentially helpful treatment is the incorporation of growth factors through gene therapy. Gene therapy removes the “bad gene” of a virus and inserts a good one, in this case the gene for growth factors, he explained.

But the effectiveness of that treatment is only one of the many unanswered questions about Alzheimer’s. The cause remains unknown, and one of the major risk factors is aging—we’re living longer, so Alzheimer’s is more prevalent, Pang said. Some people believe brain cells, and other parts of our body, weren’t designed to live so long, he said, and others think environmental toxins are to blame. He feels, however, that a number of factors, rather than a “simple reason,” are probably contributing to the increased prevalence of the disease whose mysteries he is attempting to solve. (Posted August 20, 2002)