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Unforgettable discoveries

Minnesota researchers are unraveling the mysteries of Alzheimer’s disease

When German physician Alois Alzheimer first reported in 1906 on the disease that now bears his name, he described two abnormal structures in the brain called plaques and tangles. This discovery was the beginning of a complicated mystery.

What are plaques and tangles made of? What do they do to the brain? Do they actually cause memory loss and dementia? Or are they just fingerprints left at the scene of a pathological crime?

These questions are challenging, especially since autopsied human brains can only reveal the disease in its final stages. Studies of living cells in a laboratory provide valuable insight into disease processes but may not reveal what actually happens in a person.

Karen Hsiao Ashe, M.D., Ph.D., and her research team recently identified the molecule known as A?* as the memory-impairing agent in mice modeling Alzheimer's disease. They also found that the rats' memory impairment was reversible, providing hope that

A path to new discoveries

To make sense of Alzheimer’s disease, the research community needed a living laboratory in which scientists could observe the disease from beginning to end. Enter the mighty mouse model—and the groundbreaking work of Karen Hsiao Ashe, M.D., Ph.D., professor of neurology and neuro-science at the University of Minnesota and holder of the Edmund Wallace and Anne Marie Tulloch Chairs in Neurology and Neuroscience.

Mice do not actually develop Alzheimer’s disease, but laboratory engineering with a mutated human gene can repro-duce features of the disease in mice. In 1996 Ashe and her lab team developed the first Alzheimer’s disease-like mouse in which researchers could observe both memory loss and plaques. And it was the first model made widely available, enabling scientists around the world to compare their findings.

Since then, Ashe and her team have manipulated the genetic makeup of mice to create models of different aspects of the disease. Last year, while working with a model created to develop the neurofibrillary tangles associated with demetia, they discovered that they could actually reverse memory loss. It’s a breakthrough that directly contradicts the long-held belief that the effects of Alzheimer’s disease are permanent. That research was published last July in the journal Science.

Recently Ashe’s work has yielded an even larger discovery—an answer to one of the most puzzling questions in Alzheimer’s disease research: What causes memory loss? The answer appears to be, at least in part, a tiny molecule Ashe has dubbed Aß* (or “a-beta-star” ). The team published their findings in the March 16 issue of the journal Nature.

Such discoveries are urgently needed. Right now, about 4.5 million people in the United States have Alzheimer’s, and this number could nearly triple by 2050. The University of Minnesota is well positioned to confront this crisis and to translate findings about disease-related molecules into medications that can stem the loss of memories and lives to a devastating illness.

Of mice, memory, and molecules

In 1984 scientists found that the main ingredient in the Alzheimer plaque is a minuscule protein fragment called amyloid-beta, or Aß. Since then, scientists have learned how these fragments assemble themselves into small clusters and then into larger structures that eventually form plaques. Evidence suggests that the small clusters of Aß may be the real suspects in the pathology of Alzheimer’s disease.

Sylvain Lesné, Ph.D., a postdoctoral fellow in Ashe’s lab, identified a number of these Ab clusters in the brains of the Alzheimer-like mice. Ashe’s group then assessed which of these suspects were at the scene of the crime—or which of them were abundant when the Alzheimer-like mice first began having memory problems.

The evidence pointed to Aß*. When researchers injected Aß* into healthy rats, the memory-impairing agents were caught red-handed. The rats experienced memory loss like the symptoms observed in the mouse models of Alzheimer’s disease.

Perhaps the most intriguing outcome of Ashe’s study is the hope for correcting memory problems. The memory impairment observed in the rats was reversible and occurred long before the brain was permanently damaged.

“Aß* is acting like an intoxicant,” says Ashe, “putting the neurons to sleep but not killing them.”

The implications of this discovery are profound. “If we can intervene before nerve cells are irreversibly damaged or dead, that would be a tremendous advance,” says Sam Gandy, M.D., Ph.D., a neurologist and molecular biologist at Thomas Jefferson University and chair of the Alzheimer’s Association’s Medical and Scientific Advisory Council.

“At the moment,” explains Gandy, “we’re only intervening after there are clear clinical signs and symptoms, which so far have been irreversible.” If scientists can create a drug that targets Aß*, he says, then we may eventually have a treatment to prevent, arrest, or reverse memory impairment associated with Alzheimer’s disease.

Researchers involved in the study include: (front) Karen Hsiao Ashe, Dina Nash, Colleen Forster, Lisa Kemper, and Matt Sherman; (middle) Preethi Krishnan, Linda Kotilinek, Sarah Chevaillier, Pauline Sharpe, and Jen Paulson; (back) Carol Ma, Sylvain Lesné

Of mice and humans

The Nature paper represents 14 years spent pursuing a rigorous research strategy: Replicate the disease in an animal, identify molecules present in animals with the disease and absent in those without it, isolate the molecules, and see if they cause the disease in healthy animals.

“Dr. Ashe’s paper is the quintessential demonstration of this strategy,” says Timothy Ebner, M.D., Ph.D., head of the University’s Department of Neuro-science and holder of the Maurice Visscher Land-Grant Chair in Physiology. “You really have to attack this disease at the basic level—to understand it at the molecular level. Then you have a real chance to intervene.”

Although the paper marks a critical milestone, a wide gap remains between a memory-impairing molecule in a mouse model and a prescription at a local pharmacy. The University aims to bridge that gap with the newly formed Center for Memory Research and Care. Under Ashe’s direction, the center will have three components: basic research, translational research, and clinical research and care.

The next steps in basic research include an investigation of autopsied brain tissues from people with and without memory impairment to determine if Aß* can be identified, quantified, and correlated with the individual’s degree of impairment. Ashe will coordinate this work with David A. Bennett, M.D., the primary investigator of the Religious Orders Study at Rush University Medical Center in Chicago.

Translational research will focus on developing compounds able to block the formation of Aß*, break it down, or interfere with its ability to affect brain cells. Ashe hopes to collaborate on this effort with Gunda Georg, Ph.D., who was recently recruited from the University of Kansas to lead the College of Pharmacy’s Department of Medicinal Chemistry.

Comprehensive care and clinical research

The clinical component of the center will be the Memory Clinic under the direction of J. Riley McCarten, M.D., medical director of the Geriatric Research, Education, and Clinical Center (GRECC) at the Minneapolis VA Medical Center. Scheduled to open this summer, the Memory Clinic will, first and foremost, provide comprehensive, interdisciplinary assessment and care for people with dementia and their families. It will also serve as a clinical site for testing new drugs.

S. Charles Schulz, M.D., head of the Department of Psychiatry, and his colleague David C. Anderson, M.D., head of the Department of Neurology, collaborated with University of Minne-sota Physicians to spearhead the drive for the Memory Clinic because of the Twin Cities’ need for comprehensive dementia care. One reason such clinics are uncommon is the expense. “They are terribly expensive, and the families are terribly in need,” says Anderson. “There’s a real disconnect between the revenues and the costs for running this kind of program.”

The University of Minnesota’s affiliation with the VA Medical Center’s GRECC will give the Memory Clinic an operational and scientific head start. GRECC will serve as a model for conducting clinical research and implementing evidence-based care. “By integrating the two clinics,” states McCarten, “by sharing resources and research databases, we will significantly strengthen both of them.”

He also believes the Memory Clinic, as a part of the larger Center for Memory Research and Care, will facilitate treatment advances based on Ashe’s research with mouse models.

“Because we are affiliated with such outstanding bench research,” says McCarten, “we will be able to translate that into clinical research. We are hopeful that we will—if not cure—make a significant impact on the treatment of Alzheimer’s disease.” 

By Jay D. Lenn

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