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Analyzing alzheimer’s

MU researchers continue studies with hopes to soon understand
Saturday, July 7, 2007 | 2:00 a.m. CDT; updated 9:40 a.m. CDT, Sunday, July 20, 2008
Ted Distiler, above, shares the story of his wife, Norma Jean, diagnosed with Alzheimer’s in 1993, with 12 men in an Alzheimer’s support group. His story will be published in the book “The 110,000 Missourians with Alzheimer’s.”

Ted Distiler, 70, of Jefferson City has been taking care of his wife, Norma, since she was first diagnosed with Alzheimer’s in 1993.

When Norma had surgery after hitting her head in May 2003, Distiler said, a CAT scan revealed a large number of amyloid plaques in her brain.

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“It’s almost like a horror movie,” he said, “watching the brain being eaten alive by the amyloid plaques.”

Amyloid plaques are just one of the many things researchers at MU are hoping to learn more about in the brains of Alzheimer’s patients.

A research team led by MU biochemistry professors Grace Sun and Gary Weisman and University of Minnesota professor of pharmacology W. Gibson Wood received a $6 million grant on May 1 to continue researching different ways to prevent and cure Alzheimer’s.

Alzheimer’s is the most common form of dementia among older adults and affects areas of the brain that control memory, judgment, behavior and intelligence, according to the National Institutes of Health. The disease affects 7 percent to 10 percent of people older than 65 and more than 40 percent of those 80 or older. By 2050, 25 percent of the total population of the United States will be 65 or older.

“It’s a problem,” Sun said. “Anything that we can do to shorten it or delay it would be good.”

The grant was awarded by the National Institute of Aging to fund research for the next five years.

“It’s an accomplishment to be renewed,” Weisman said. “In five years, we hope to make more progress towards understanding this disease.”

For the past five years, the project relied on another $5 million grant from the National Institute of Aging and needed the new grant in order to continue the research, Sun said.

Previous research has allowed researchers to recognize two major abnormalities in the mechanisms of a brain affected by Alzheimer’s.

First, they have recognized that the release of a protein called an amyloid-beta peptide, or A-beta, is produced in excess amounts. For unknown reasons, this increase in A-beta becomes toxic in brain cells of people with the disease.

Second, they have recognized that A-beta can increase oxidative stress and enhance inflammatory responses in the brain, which can lead to the development of the disease. These are not new mechanisms, Sun said, but the researchers have been able to obtain new information to better understand these processes.

A-beta is a protein made up of 39 to 42 amino acids that is released from a larger protein called the amyloid precursor protein. Recent studies demonstrate that when A-beta is released from cells, it may become toxic. After it releases its toxins, it accumulates in amyloid plaques.

Through autopsies, researchers have been able to learn that people who suffered from Alzheimer’s had an increased number of amyloid plaques, Sun said. She believes understanding the mechanisms that affect this abnormal release of A-beta and how it changes to become toxic are important factors toward understanding the progression of this disease.

Researchers will also continue to investigate how reactive oxygen radicals are produced in brain cells and how brain cell functions are affected by A-beta. Specifically, they will study in detail how A-beta becomes toxic and how toxicity is linked to neuronal impairments, leading to loss of memory and cognitive functions.

“Our studies involve biochemical and molecular techniques and utilize cell models,” Sun said. “Without this grant, it is impossible to carry out expensive experiments.”

The three researchers’ future experiments will continue for the next five years through three separate projects. Their goal as a team, Weisman said, is to learn how to block inflammation in the brain and decrease the negative effects of A-beta. He hopes the work they do will play a big role in fighting the disease and help develop the foundation for drug treatment in many inflammatory diseases, not just Alzheimer’s.

Sun will begin her next phase of research by heading a team that will study how A-beta destroys brain cells by activating phospholipid enzymes. Her research, she said, is based on recent evidence that A-beta increases those harmful enzyme reactions.

Weisman and his team will look at preventing chronic inflammation in the brain as well as A-beta production by using a certain protein receptor, called P2Y2, as a target.

“Our immune system is there to protect us,” Weisman said. “Chronic inflammation, however, ends up killing you.”

In chronic inflammation, Weisman said, the immune system attacks tissues in the body because the immune cells are led to believe the tissues are foreign invaders. The P2Y2 receptor protein, which appears on cells during early stages of inflammation for unknown reasons, causes the appearance of other proteins that attract immune cells. The resulting immune system attack scars the brain as a result.

Over the next five years, Weisman will try to find out how much the receptor protein is involved in Alzheimer’s as well as how important it is in the development of the disease.

The receptor protein “is one of many targets in potential Alzheimer’s therapies and the new one on the block,” Weisman said.

To conduct his research, Weisman and his team are using lab mice and other animals with Alzheimer’s. A particular line of mice that develop amyloid plaques at an early age is used, Sun said.

“We will be using this mouse model to examine biochemical and behavioral abnormalities with regard to severity of plaque deposit,” she said.

At the University of Minnesota, Wood is looking at the controversial use of statins, or cholesterol lowering drugs, to prevent or treat Alzheimer’s as well as other brain diseases such as multiple sclerosis, ischemic stroke and AIDS dementia.

Statins, Wood said, have been shown to protect brain cells in different experimental conditions. Previous research has found that simvastatin, a cholesterol-lowering drug, increases the Bcl-2 gene expression and protein levels. Bcl-2, he said, prevents programmed cell death. With these findings, Wood hopes to “determine if effects of simvastatin on Bcl-2 gene expression and protein levels is cholesterol dependent or independent.”

One of the biggest rewards for this project, Sun said, is its ability to attract other faculty and scientists on the MU campus to become interested in Alzheimer’s research.

“In fact, the collaboration led to funding of another National Institutes of Health grant and an Alzheimer’s grant to Dr. James Lee in the Biological Engineering Department,” she said. “We hope that our program will become a catalyst to stimulate more research on campus and to generate more support by the state.”

Weisman believes general knowledge of the approximately 30,000 genes and related proteins in the body will help contribute to the group’s overall work. Each gene and each protein, he said, are like jigsaw puzzles, and he and other researchers worldwide are in the process of assembling those pieces into an overall picture of the human body.

“We are making an owner’s manual for the body that we didn’t have available when we were born,” Weisman said.

Taking the lead

These men have seen their world turned upside down.

Taking on the role of caregiver is the focus of a local support group for men taking care of women in their lives dealing with Alzheimer’s.

Between 15 and 20 men meet from 11 a.m. to 1 p.m. on the third Thursday of every month in the basement of Primaris Healthcare Business Solutions, 200 N. Keene St., to discuss their roles as Alzheimer’s caregivers and learn from each other.

The group, called Changing Places: Men as Emerging Caregivers, is facilitated by the Alzheimer’s Association Mid-Missouri.

Family Services Specialist Sarah Beck of the Alzheimer’s Association believes the group is unique because it brings together men in an unfamiliar role as caregivers for women. Since its beginning in fall 2004, she estimates more than 40 men have participated.

The men learn how to provide better care by talking about a variety of subjects, occasionally offering advice and sometimes sharing stories of similar experiences with one another.

In last month’s meeting, members shared their thoughts about what to do when the woman they’re helping asks to go home when she’s already there. The men bounced ideas off each other and came up with a consensus of telling their loved ones they are going home tomorrow. If that happens every day, the group decided, the best approach is to repeat what was said the day before.

For information about the support group, contact Sarah Beck of the local Alzheimer’s Association at 443-8665.


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